Stem Cell Therapy: A Primer for Interventionalists and Imagers

 
 
Stem Cell Therapy: A Primer for Interventionalists and Imagers
Emerging Technologies




Stem Cell Therapy: A Primer for
Interventionalists and Imagers
Boris Nikolic, MD, MBA,* Salomao Faintuch, MD, S. Nahum Goldberg, MD, Michael D. Kuo, MD, and
  John F. Cardella, MD


In recent years, research advancement in stem cell therapy has been rapid. Accordingly, general clinical, scientific, and
public attention to the application of stem cell therapy has been substantial. Promises are great, most notably with
regard to the application of stem cell therapy for diseases that are currently difficult to treat or incurable such as
Parkinson disease or diabetes mellitus. It is in the best interest of patient care for diagnostic and interventional
radiologists to be actively involved in the development of these therapies, both at the bench and at the bedside in clinical
studies. Specifically, the diagnostic radiologist can become an expert in imaging, tracking, and monitoring of stem cells and
in the assessment of engraftment efficiency, whereas the interventionalist is a natural expert in targeted stem cell delivery
by means of different routes (percutaneous, selective intravenous, or intraarterial). In addition, there is a potential role for
the interventionalist to create engraftment territory and increase engraftment bed fertility with controlled intentional tissue
destruction (eg, by means of thermal ablation) that might precede stem cell administration.

J Vasc Interv Radiol 2009; 20:999 –1012

Abbreviations:    MS ⫽ multiple sclerosis, RF ⫽ radiofrequency, SPIO ⫽ superparamagnetic iron oxide



RESULTS of recent stem cell research                     properties and potential therapeutic           sion. They are of more limited differen-
have received much clinical, scientific,                 applications. Radiology may play a             tiation ability and destined to develop
and public attention, and clinical ap-                   pivotal role in stem cell delivery, stem       into cells of a specific organ, tissue, or
plications of stem cell therapy will un-                 cell engraftment monitoring through            organ system with the (potential) ability
doubtedly continue to expand in the                      imaging, and, potentially, improve-            to fulfill corresponding functions (Fig 1
future. The interventional and diag-                     ment of engraftment conditions with            [2]). Adult stem cells can be harvested
nostic radiologist should be familiar                    use of minimally invasive procedures,          from bone marrow, adipose tissue, and
with the basic principles of stem cell                   as will be shown below.                        umbilical cord blood. Examples of adult
                                                             Stem cells have the ability to divide      stem cells are hepatic progenitor cells,
                                                         and self-renew indefinitely as well as to      which have the capability to differenti-
From the Department of Radiology, Beth Israel Dea-       differentiate into one or more cell types      ate into hepatocytes, or type II pneumo-
coness Medical Center–Harvard Medical School,            (1). It is relevant to differentiate between   cytes, which have the potential to differ-
One Deaconess Rd, West CC Bldg, 3rd Fl, Boston,
MA 02215 (B.N., S.F., S.N.G.); Department of Radi-       the various types of stem cells— dis-          entiate into parenchymal lung cells (Fig
ology, UCSD Medical Center School of Medicine,           cussed below in greater detail—and to          1 [2]). It is notable that ethical concerns
San Diego, California (M.D.K.); and System Radiol-       distinguish between embryonic stem             surrounding stem cell research are
ogy, Geisinger Health System, Danville, Pennsylva-       cells, which are obtained from the inner       mostly related to embryonic stem cells.
nia (J.F.C.). Received April 16, 2009; final revision
received April 24, 2009; accepted April 28, 2009.        cell mass of the blastocyst, and adult         A comprehensive ethical discussion
Address correspondence to B.N.; E-mail: boris.nikolic@   stem cells, which are found in adult so-       about the use of human embryonic stem
uphs.upenn.edu                                           matic tissue. The only types of stem cell      cells is clearly beyond the scope of this
*Current affiliation and corresponding author con-       that are pluripotent (ie, may differenti-      article. Briefly, however, the pursuit of
tact: Boris Nikolic, MD, MBA, Hospital of the Uni-       ate into any cell type) are embryonic          the undisputedly ethical end of allevia-
versity of Pennsylvania, University of Pennsylvania      stem cells (Fig 1 [2]). Embryonic stem         tion or cure of human suffering conflicts
School of Medicine, Department of Radiology, Sec-        cells subsequently develop into partially      in this case with the means of destruc-
tion of Interventional Radiology, 3400 Spruce Street,
1 Silverstein, Philadelphia, PA, 19104; E-mail:          differentiated stem cells that may in          tion of embryonic tissue—an act that
boris.nikolic@uphs.upenn.edu                             turn give rise to several different cell       many regard as an unacceptable viola-
                                                         lines, but these cells can no longer be-       tion of respect for human life.
None of the authors have identified a conflict of
interest.                                                come any type of cell (ie, they are mul-           Adult stem cells, such as those de-
                                                         tipotent stem cells) (Fig 1 [2]). Adult        rived from bone marrow (subdivided
© SIR, 2009
                                                         stem cells are multipotent cells as well       into hematopoetic and mesenchymal/
DOI: 10.1016/j.jvir.2009.04.075                          and the result of further lineage progres-     marrow stromal cells), are classically


                                                                                                                                              999
Stem Cell Therapy: A Primer for Interventionalists and Imagers
1000   •   Primer on Stem Cell Therapy                                                                                August 2009      JVIR




Figure 1. Simplified representation of stem cell differentiation. Cell differentiation progresses from the center toward the periphery.
The green center includes blastocyst and pluripotent cells. The yellow area includes cells developed from embryonic stem cells, which
have a capacity to differentiate into many different cell types but are more restricted than embryonic stem cells. Cells in the gold area
are the result of further lineage progression, generally destined to develop into a certain cell type such as hepatic progenitor cells into
hepatocytes or type II pneumocytes into parenchymal lung cells. ? denotes potential crossing of individual cell populations to
differentiate into specialized cells of organs derived from other germ layers; this crossing ability is somewhat controversial but can likely
occur under certain circumstances. Adapted and reprinted from Biochimica et Biophysica Acta, 1782, M. Oertel and D. Shafritz, Stem
cells, cell transplantation and liver repopulation, 61–74, 2008, with permission from Elsevier.



harvested as autologous cells and are           led to Nobel Prize recognition of Jo-           atosus, or amyloidosis as well as
generally free of ethical controversy.          seph E. Murray’s and E. Donnall                 other blood dyscrasias. It is per-
With recent demonstration of the abil-          Thomas’ work in managing trans-                 formed 30,000 – 40,000 times each
ity to reprogram human somatic cells            plant rejection and graft-versus-host           year, increasing in use annually, and
to cells with embryonic stem cell type          reaction as well as performance of              there are more than 20,000 individu-
differentiation potential with trans-           transplantation of hematopoetic                 als who have survived at least 5
duction of certain defined transcrip-           stem cells, respectively. Autologous            years after hematopoetic stem cell
tion factors, ethical concerns can be           or allogeneic hematopoetic stem cell            transplantation (5).
expected to lessen and opportunities            transplantation is now a routine pro-               However, not all forms of utilization
to use stem cells for therapy will likely       cedure and is successfully used clin-           of stem cells in clinical care have en-
expand in the future (3,4).                     ically for the treatment of diseases            dured. Specifically, stem cell adminis-
   Although stem cells have received            such as lymphoma, multiple my-                  tration to overcome bone marrow toxic-
much research attention recently, the           eloma, leukemia, neuroblastoma,                 ity from high-dose chemotherapy as
first successful transplantation of             germ cell tumors, certain types of              practiced in the early 1990s has been
bone marrow– derived hematopoetic               anemias such as sickle cell disease or          largely abandoned due to short periods
stem cells dates back to the late               aplastic anemia, autoimmune disor-              of therapeutic response and high mor-
1960s. Translational research later             ders such as systemic lupus erythem-            tality rates (6,7). More recent experi-
Volume 20      Number 8                                                                                       Nikolic et al     •   1001


ments have focused on the use of stem            man clinical trials are occurring or         ROLE OF THE
cells for the therapy of different organs        are under way in some areas, only            INTERVENTIONAL AND
and organ systems beyond blood dys-              preliminary experimental data that           DIAGNOSTIC RADIOLOGIST
crasias and autoimmune disorders (5).            oftentimes have been obtained from
Multiple studies have shown the ability          animals are currently available in               One may wonder what role the in-
of stem cells of various origins to differ-      others. For instance, stem cell ther-        terventional radiologist and/or im-
entiate into specialized, fully functional       apy has been routinely used for some         ager may have in research and clinical
parenchymal cells both in vivo and in            time in the treatment of leukemia            application of stem cell therapy. It
vitro (8 –12).                                   and lymphoma (58) and is in the              seems prudent for all radiology pro-
    The general capacity of stem cells to        early stages of clinical investigation       fessionals to approach stem cell re-
repair damaged tissue and restore func-          for the treatment of cardiac disease         search not in an attempt to capture a
tion that would otherwise be lost irre-          and diabetes mellitus (59,60) as well        piece of the pie of an emerging field of
versibly has been demonstrated numer-            as certain neurologic disorders such         promising research. Instead, radiolo-
ous times and has fueled recent research         as MS and stroke (22,61), whereas it         gists should determine their respective
efforts to use undifferentiated living           has not (yet) undergone the transla-         roles as the most qualified expert con-
cells to maintain, improve, or recover           tion from bench to bedside applica-          tributor for certain steps in the process
organ function in lieu of organ trans-           tion for some other entities and or-         of stem cell research and clinical ap-
plantation or while lacking other treat-         gan systems such as certain lung             plication of stem cell therapy. Even
ment options. For instance, stem cells of        diseases (52). Consequently, stem            though stem cell research efforts have
various origins have successfully been           cell therapy may soon become rou-            been scarce in all radiology, there are
used to alleviate pulmonary hyperten-            tine clinical reality in some areas,         indeed such roles in this research field
sion in dogs, restore biochemical func-          whereas only hope and promise cur-           that is rapidly progressing and will in-
tion of the liver in an animal model of          rently exist in others. As will be           evitably further implement itself into
tyrosinemia 1, or regenerate axons               shown, a plethora of experimental            clinical practice and patient care. Suc-
through chronically denervated periph-           data have produced partially incon-          cessful stem cell transplantation gener-
eral nerves (8,9,13).                            sistent results, most of which have          ally consists of adequate stem cell har-
    General additional areas of research ef-     been attributed to methodologic dif-         vesting, trafficking to the desired target
forts include the use of stem cells for the      ferences such as variations in stem          area, full stem cell differentiation, and
treatment of degenerative neurologic dis-        cell delivery route and stem cell ad-        significant—and ideally sustainable—
orders such as Parkinson and Alzheimer           ministration timing. In fact, it ap-         contribution to organ function. The stem
disease and motor neuron disorders,              pears that successes in stem cell ther-      cell trafficking process has been subdi-
stroke, multiple sclerosis (MS), and acute       apy mandate profound knowledge of            vided into cell homing, that is, directed
injury of the spine (14–24). Stem cell utili-    stem cell properties and harvesting, cell    blood dispersion of stem cells, and in-
zation has been considered for musculo-          trafficking, and engraftment bed recep-      terstitial migration, which generally oc-
skeletal regeneration such as the repair of      tiveness as well as cell engraftment effi-   curs within a confined territory within a
nonhealing fractures and rebuilding of           ciency and subsequent engraftment            given organ (63). Clearly, the interven-
degenerated cartilage or tendons (25–28).        monitoring. On the basis of this type of     tionalist should have a pivotal role in
In addition, stem cell treatment of myo-         knowledge, it may be possible to prop-       targeted stem cell delivery to certain or-
cardial infarction and heart failure to im-      erly select stem cell type, administration   gans such as the pancreas, liver, or kid-
prove cardiac function and performance           timing and delivery route for specific       ney. The interventionalist’s partici-
has been explored (29,30). Stem cell–            disease entities, anatomic areas, and        pation may overcome some of the chal-
based alleviation or correction of liver dis-    physiologic circumstances to accom-          lenges that are currently associated with
ease has been sought (2,9,10,31–35). Stem        plish the distinction between general-       stem cell homing. In particular, selective
cell potential is being tested to treat diabe-   ized unsubstantiated claims pertaining       and direct stem cell release to the target
tes (36–45). Additionally, stem cell ther-       to stem cell and reproducible experi-        organ by means of transcatheter intraar-
apy has shown promise in promoting               mental and clinical therapeutic suc-         terial delivery may overcome potential
wound healing and improving perfusion            cesses.                                      mechanical barriers caused by liver cir-
in the setting of limb ischemia (46–49).            A very interesting yet poorly devel-      rhosis and fibrosis that have been pos-
Furthermore, stem cell administration has        oped area of stem cell research is the       tulated to exist for nonselective stem cell
been contemplated to alleviate pulmo-            concept of utilization of stem cells as      delivery techniques (64). In this context,
nary disorders such as chronic obstructive       vehicles for gene and drug delivery.         recipient organ perfusion with donor
pulmonary disease (50–53). The treatment         This area holds great promise because        cells “via a radiologically placed cathe-
of miscellaneous disorders such as sclero-       viable cells that are administered have      ter” has been recommended by a prom-
derma, retina degeneration, and inner ear        the properties to adjust, multiply, mi-      inent stem cell expert (64). Indeed, in a
as well as renal disorders has also been         grate, and communicate with adjacent         recent clinical study, hepatic regen-
researched (54–57).                              cells. For instance, Sha et al have shown    eration could be enhanced with por-
    The current state of knowledge               that injected mouse neural precursor         tal venous infusion of bone marrow–
and type and extent of available data            cells had the ability to migrate to the      derived stem cells into portal vein
vary considerably in these men-                  contralateral brain hemisphere and de-       branches before portal vein emboli-
tioned fields of clinical and experi-            liver cytotoxic tumor therapy to glioma      zation and partial hepatectomy (65).
mental stem cell applications and                foci, thereby reducing tumor growth              As mentioned, some discrepancies
across specific entities. Although hu-           (62,63).                                     of experimental results of significant
1002   •   Primer on Stem Cell Therapy                                                                            August 2009     JVIR



                                                                                             studies have been performed for the
                                                                                             purpose of stem cell tracking and have
                                                                                             shown that superparamagnetic iron ox-
                                                                                             ide–labeled stem cells can be visualized
                                                                                             with magnetic resonance (MR) imaging
                                                                                             by causing signal drop-out on T2*-
                                                                                             weighted sequences and strong effects
                                                                                             at R2* mapping, respectively (71–79)
                                                                                             (Figs 2, 3 [79,80]). This tracking ability
                                                                                             has been exploited to demonstrate glo-
                                                                                             merular homing of magnetically labeled
                                                                                             stem cells in a rat model of nephropa-
                                                                                             thy, in vivo imaging of magnetically la-
                                                                                             beled stem cells in the liver, and map-
                                                                                             ping and monitoring of injected stem
                                                                                             cells in the setting of stroke and brain as
                                                                                             well as spinal cord injury. In the context
                                                                                             of these studies, the capacity of stem
Figure 2. T2*-weighted MR images of one Balb/c mouse before injection, one Balb/c            cells to migrate or home to the area of
mouse 24 hours after injection (p.i.) of 3 ⫻ 107 ferumoxide-labeled progenitor cells, and    damaged renal and brain tissue has
one Balb/c mouse 24 hours after injection of ferumoxide (without cells). The labeled cells
                                                                                             been demonstrated. Future study of MR
distribute differently than does the pure contrast medium. The amount of administered
iron was 20 ␮g through injection of iron oxide–labeled cells and 25 ␮g through injection     imaging– based labeled stem cell track-
of the pure contrast medium (the latter applies to the usual clinical dose). MR images of    ing should further advance the knowl-
the body show the liver with the left hepatic lobe extending across the midline (curved      edge of in vivo distribution, migration,
solid arrow) and spleen (open arrow). Below that, MR images were reconstructed along         and engraftment of stem cells and result
the long axes of the femora, in which the corticalis (arrowhead) and the bone marrow         in clinical monitoring of stem cell ther-
(straight solid arrow) can be clearly delineated. The ferumoxide-labeled cells caused a      apy in certain anatomic areas.
marked decrease in signal intensity in the liver, spleen, and bone marrow, whereas              Modalities that have been used for car-
injection of the pure contrast medium caused visible signal intensity changes in the liver   diac stem cell imaging include optical im-
and spleen but not the bone marrow. Reprinted from Radiology, 234, H. Daldrup-Link, M.       aging, single-photon emission computed
Rudelius, G. Piontek et al, Migration of iron oxide-labeled human hematopoietic progen-
itor cells in a mouse model: in vivo monitoring with 1.5-t MR imaging equipment,
                                                                                             tomography (SPECT), positron emission
197–205, 2005, with permission from Radiological Society of North America.                   tomography (PET), MR imaging, and
                                                                                             multimodality imaging, that is, the use
                                                                                             of multimodality contrast media. Opti-
                                                                                             cal imaging encompasses biolumines-
differentiation of administered stem          during moments of injurious stress to          cent and fluorescent techniques. With
cells have occurred and have partly           certain organs (69,70).                        bioluminescence, light is generated by
been attributed to a nonselective                In the setting of acute organ injury,       the enzyme luciferase (81– 83). This
route of stem cell administration             stem cell trafficking could likely be fur-     technique is limited by the facts that
(systemic vs transportal), further un-        ther enhanced by optimizing timing of          only visible light is generated (400 –700
derscoring the relevance an interven-         stem cell administration, which likely         nm), luciferase genes and substrates are
tionalist could have in stem cell de-         occurs if it is synchronized with peak         associated with very high absorption
livery (66 – 68).                             levels of certain key cytokines. How-          and scatter, and no animals larger than
   An additional relevant parameter           ever, the key cytokines that regulate          rats have been imaged with this meth-
with regard to stem cell engraftment          stem cell trafficking for various target       odology with satisfactory accuracy
success is the target area receptiveness      organs must also be further investigated       (84,85). In fluorescence imaging, cells
for stem cells after their respective ad-     in terms of their respective release           are labeled with organic (green fluores-
                                              mechanisms and role as well as their           cence protein, small molecule polyme-
ministration. Depending on the type of
                                              respective interaction with each other. A      thines) or organic/inorganic hybrid
target organ and stem cell type that is
                                              description and analysis of the various        (quantum dots) agents for in vivo detec-
used, infliction of acute organ injury is
                                              key cytokines is clearly beyond the            tion (86). Limitations with this technique
known to be necessary for cell traffick-      scope of this article but has been de-         include spatial limitations of imaging
ing and differentiation, the former of        scribed elsewhere (63,69). The types and       capabilities to a tissue depth of 4 –10 cm,
which is triggered by the release of cer-     respective roles of certain cytokines dif-     dilution of contrast signal due to subse-
tain key cytokines (31,32,35). Interest-      fer across different organs, and an excel-     quent cell divisions, and possible stem
ingly, substantial mobilization of bone       lent example of effects on expansion,          cell uptake by macrophages after stem
marrow– derived stem cells has been           proliferation, and/or mitogenesis of           cell death (87).
demonstrated after myocardial infarc-         specific key cytokines on oval cells dur-         Stem cell imaging with SPECT is
tion in humans and liver injury in ro-        ing activation of stem cells in hepatic        performed by detecting high-energy
dents, which has been interpreted as          disease is given by Bird et al (69).           ␥-rays emitted by technetium 99m
persistence of a more primitive self-            A role for imaging of stem cell ther-       (99Tc), indium 11, or iodine 123, which
repair mechanism of viable organisms          apy is likewise developing. Numerous           are introduced by direct radiometal
Volume 20    Number 8                                                                                Nikolic et al      •   1003




                                                                                     Figure 3. (a– e) T2-weighted gradient-
                                                                                     echo MR images show signal intensity
                                                                                     changes of the liver after injecting la-
                                                                                     beled (top row) and unlabeled (bottom
                                                                                     row) bone-marrow-derived stem cells (a) 3
                                                                                     hours before and (b) 3 hours, (c) 3 days,
                                                                                     (d) 7 days, and (e) 14 days after injection.
                                                                                     Note the gradual return of signal intensity
                                                                                     compared with that before transplantation
                                                                                     and in control rats. *Signal intensity
                                                                                     changes of the liver. Reprinted from Radi-
                                                                                     ology, 245, S. Ju, G. Teng, H. Lu, et al, In
                                                                                     vivo MR tracking of mesenchymal stem
                                                                                     cells in rat liver after intrasplenic trans-
                                                                                     plantation, 206 –215, 2007, with permission
                                                                                     from Radiological Society of North America.




loading, enzymatic conversion with             Enzymatic conversion and reten-       PET has shown only a fraction of
retention of a radioactive substrate, or    tion implies enzyme introduction         stem cells (1.3%–2.6%) around the in-
receptor-mediated binding (88 –93).         through a transgene. This technique      farction border within 1–1½ hours
Although visualization of 99Tc radio-       has been used for SPECT as well as       after intracoronary injection. At-
metal-loaded stem cells has been ac-        PET imaging and is characterized by      tempts have been made to overcome
complished up to 4 hours after cell         the ability of indefinite in vivo stem   the limited half-life of fluorine (110
infusion in a rat model of myocardial       cell monitoring without effects of       minutes) by integrating a mutant
infarction, limitations of this technique   signal dilution by stem cell division    herpes simplex type 1 thymidine ki-
include the trade-off between half-life     but requires expression of a unique      nase into stem cells followed by pe-
and long-term exposure to ionizing ra-      stable receptor (93,94). The sensitiv-   riodic intravenous injection of thy-
diation as well as potential of the ra-     ity of SPECT is high when compared       midine kinase substrate and serial
diometal transfer to non-stem cells         with that of optical imaging and MR      image acquisition over time. This
(87,90).                                    imaging. Limited experience with         technique, however, is hampered by
1004   •   Primer on Stem Cell Therapy                                                                            August 2009     JVIR



                                                MR imaging, ultrasonographic, and            most advanced, and/or most relevant
                                                fluorescence contrast media (98,99).         for the diagnostic and/or interven-
                                                    On a more cautionary note, a sepa-       tional radiologist.
                                                rate but also noteworthy area of stem
                                                cell research is the identification and      Stem Cells for Liver Disease
                                                recognition of cancer stem cells. The
                                                cancer stem cell paradigm postulates             The liver possesses tremendous re-
                                                that a minority of cancer stem cells are     generative potential, and mature hepa-
                                                tumorigenic and give rise to tumor re-       tocytes in transgenic mice may divide at
                                                lapse, metastasis, and de novo tumor         least 69 times (104,105). Hence, hepato-
                                                formation whereas the more differen-         cytes have a property similar to that of
                                                tiated tumor bulk is nontumorigenic.         stem cells, although they do not share
                                                Indeed, cancer stem cells have been          the characteristic of stem cell immortal-
                                                found in malignancies of the breast,         ity. However, the remarkable regenera-
                                                brain, colon, pancreas, and liver. In        tive potential of the liver may be
                                                fact, ␣-fetoprotein, a well known and        blocked or insufficient in settings of in-
                                                clinically routinely used marker for         trinsic liver disease, in which case stem
                                                hepatocellular carcinoma, is a marker        cell– based liver regeneration is a prom-
                                                of fetal hepatocytes (69,100 –103). Even     ising treatment alternative to liver trans-
                                                though the existence of cancer stem          plantation because the latter is substan-
                                                cells offers great potential for more ef-    tially morbid, is costly, is limited by
Figure 4. T2-weighted MR image of au-           fective approaches to cancer therapy,        inadequate donor supply, and neces-
tologous pig bone marrow mesenchymal            it may also harbor substantial risks for     sitates life-long immunosuppression.
stem cells labeled with Feridex (Bayer, Le-     the use of stem cells for the purpose of     Stem cell– based therapy for metabolic
verkusen, Germany) (arrows) and injected in
the anterior left ventricular wall. Image was
                                                tissue engineering, particularly in the      liver disease has been the focus of much
obtained 4 weeks after injection. Reprinted     setting of benign disease. It is currently   attention, particularly since Lagasse et al
from Trends in Cardiovascular Medicine, 15,     uncertain whether cancer stem cells          (9) restored the biochemical function of
E. Chemaly, R. Yoneyama, J. Frangioni, and      originate from stem cells that are devoid    the liver in an animal model of tyrosine-
R. Hajjar, Tracking stem cells in the cardio-   of the regulation of proliferation or        mia. This therapeutic success had been
vascular system, 297–302, 2005, with permis-    whether they arise from more differen-       accomplished with hematopoetic stem
sion from Elsevier.                             tiated progenitor cells that have trans-     cells by Jang et al (106), who found he-
                                                formed to self-renewing cells. The an-       matopoetic stem cell conversion into
                                                swer to this question is crucial to the      liver cells within days. However, some
stem cell radiation and the necessity           safe use of stem cells, and the phe-         experimental failures of significant
of genetic stem cell manipulation.              nomenon of carcinogenesis of stem            hepatocytic differentiation of adminis-
    MR imaging is the most validated            cells warrants great caution in the          tered bone marrow– derived stem cells
modality for cardiac stem cell tracking         pursuit of therapeutic stem cell use.        have also occurred. Although this has
as well and has been applied in T2/T2*          In addition, careful follow-up exclu-        been attributed to inadequate timing of
technique after stem cell labeling with         sion of any potential unwarranted            liver injury or a suboptimal route of
superparamagnetic iron oxide (SPIO)             development of malignancy along              stem cell administration (systemic vs
particles (Fig 4) (95–97). In cardiac im-       with every successful accomplish-            transportal), the potential for hepatic
aging, SPIO-labeled mesenchymal stem            ment of stem cell–induced tissue en-         differentiation of hematopoetic stem
cells have generated optimal imaging            gineering is mandatory.                      cells has been generally questioned by
results up to 8 weeks after delivery fol-                                                    some investigators (66 – 68,107).
lowing myocardial infarction in the                                                              Embryonic stem cells have the ca-
swine model (96,97). Limitations of             CURRENT STATUS OF                            pacity to differentiate into hepatocytes
SPIO labeling include SPIO-induced ar-          KNOWLEDGE: SUCCESSES                         in vitro and have been successfully
tifact, potential false-positive results        AND LIMITATIONS FOR                          transplanted into the acutely injured
caused by contrast medium uptake of             SPECIFIC ORGANS AND                          liver, leading to functional recovery
macrophages after stem cell death, and          DISEASE ENTITIES                             (10,32). However, the use of embry-
recently alleged SPIO-related stem cell                                                      onic stem cells generates ethical con-
differentiation inhibitions (87).                  Among the many areas of active            cerns and implies the risk of cancero-
    Multimodality imaging is an at-             stem cell research, the current status of    genicity. Last, liver progenitor cells
tempt to overcome limitations of indi-          knowledge is exemplified by a de-            may be considered for cell transplan-
vidual imaging techniques through               scription of the application of stem cell    tation. Four types of progenitor cells
the use of multimodality contrast me-           research for liver, cardiac, and neuro-      have been described: oval cells, small
dia. In this context, optical/MR imag-          logic diseases/disorders and the pur-        hepatocytes, liver epithelial cells, and
ing agents have been developed that             suit of primary therapy of diabetes          mesenchymal-like cells (108). Oval cells
use visible wavelengths in conjunction          mellitus (ie, restoration or improve-        originate from the biliary tree after in-
with gadolinium 3⫹ chelators conju-             ment of endocrine pancreatic func-           jury but have also been found in normal
gated to dextran as well as nanopar-            tion). In these areas, the therapeutic       liver, are named after their shape in ro-
ticles that are simultaneously usable as        use of stem cells is most illustrative,      dents, and have bipotent differentiation
Volume 20     Number 8                                                                                         Nikolic et al      •   1005




                                                                                                Figure 5. (a,b) Antibody-stained fluores-
                                                                                                cent images obtained after RF ablation
                                                                                                (original magnification, ⫻20 objective; 0.7
                                                                                                zoom) show stem cell uptake at the coag-
                                                                                                ulation margin with fluorescent stem cells
                                                                                                (arrows), coagulation area (A), and more
                                                                                                peripheral hepatic parenchyma not sub-
                                                                                                jected to substantial changes from RF ab-
                                                                                                lation heating (C). Focal blue areas of
                                                                                                fluorescence represent 4=6-diamidino-2-
                                                                                                phenylindole stain of nuclei as anatomic
                                                                                                markers and are unrelated to stem cell
                                                                                                labeling. (c,d) Gray scale images obtained
                                                                                                from light microscopy shows the zonal
                                                                                                distribution: coagulation necrosis: zone A
                                                                                                (A); peri-ablational area exhibiting maxi-
                                                                                                mal stem cell uptake: zone B (B); and
                                                                                                more peripheral hepatic parenchyma:
                                                                                                zone C (C). (e) Typical examples of he-
patic control tissue obtained from the same animal as in (a) and (b) (magnification, ⫻20 objective; 0.7 zoom). Fluorescent stem cells
(arrows) are identified in a random pattern and are much less concentrated than that seen around an area of RF ablation (cf a,b). Focal
blue areas of fluorescence represent 4=6-diamidino-2-phenylindole stain of nuclei as anatomic markers and are unrelated to stem cell
labeling. Images are from the same animal but from different lobes: radiofrequency ablation area, right hepatic lobe; and control tissue,
left hepatic lobe. Reprinted from Journal of Vascular and Interventional Radiology, 20, N. Boris, E. Mostafa, M. Pawel, et al, The effect
of hepatic radiofrequency ablation on stem cell trafficking in the rat model, 640 – 647, 2009, with permission from Elsevier and Society
of Interventional Radiology.


potential into liver as well as biliary        graftment research investigations to           ablation area in significantly higher
cells. Liver epithelial cells have similar     which the interventional radiologist           numbers than to the remaining liver—
differentiation characteristics as oval        could greatly contribute. Hence, stem          specifically to the peri-ablational margin
cells and are likewise found in healthy        cell trafficking to an injurious site has      (Fig 5). Hence, the interventionalist may
liver (109). Mesenchymal-like cells have       been exploited by creating target organ        also be able to enhance stem cell traffick-
broader differentiation potential, exhibit     injury models, such as carbon tetrachlo-       ing through performance of minimally
high levels of proliferation, and have         ride injection or performance of partial       invasive procedures in addition to as-
been isolated from adult liver (110).          hepatectomy in rodents (10,33,112). Par-       suming a pivotal role in targeted stem
Small hepatocytes have been found in           tial hepatectomy, however, subtracts           cell delivery by stem cell delivery via
healthy adult liver as well and have he-       from the overall liver volume and is           the transarterial route (113).
patocyte differentiation as well as high       highly invasive and carbon tetrachlo-
proliferation potential (111).                 ride injection is difficult to control, is     Cardiovascular Applications
   Interestingly, the presence of acute        carcinogenic, and has no therapeutic ap-
liver injury is known to greatly promote       plication. In pursuit of a more controlla-        Cardiac stem cell research in recent
stem cell differentiation and engraft-         ble, minimally invasive, clinically well-      years has focused on bone marrow–
ment within the liver. This finding, in        established and repeatable technique of        derived and embryonic stem cells and
conjunction with the dual blood supply         causing liver injury, radiofrequency           has been driven by attempts to address
and the substantial tolerance to injury of     (RF) ablation has been performed and           the unmet clinical need to treat myocar-
this organ, makes the liver an ideal tar-      coupled with subsequent stem cell injec-       dial infarction and heart failure (114).
get for stem cell delivery technique,          tion, resulting in proof of the concept        Initial studies had indeed demonstrated
stem cell trafficking, and stem cell en-       that stem cells are trafficked to the RF       transdifferentiation of bone marrow
1006   •   Primer on Stem Cell Therapy                                                                          August 2009    JVIR



stem cells into cardiomyocytes and res-       Cardiovascular progenitor cells become       delivery route, the most efficient way of
toration of cardiac function in mice after    cardiomyocytes or vascular progenitor        cell delivery is uncertain as is the opti-
the occurrence of mycocardial infarction      cells, the latter of which can progress      mal dose and the cell type and cell (sub)
(115). However, more recently bone            into smooth muscle cells (pericytes) or      population that should be used for the
marrow stem cell–to– host-cardiomyo-          endothelial progenitor cells. Hemangio-      treatment of critical limb ischemia.
cyte fusion rather than stem cell differ-     blasts may mature to hematopoetic or         Hence, these aspects should be the fo-
entiation was found to be the underly-        endothelial progenitor cells (11). Blood     cus of future investigations.
ing engraftment mechanism, and recent         flow that is required for wound healing
randomized controlled clinical trials         may be derived from angiogenesis, a          Neurologic Diseases
have failed to show significant increases     process of wound-adjacent resident en-
in left ventricular ejection fraction after   dothelial cell migration followed by             The in vivo neural stem and progen-
the injection of autologous bone mar-         neovessel creation that is accomplished      itor cell has been identified as an astro-
row– derived stem cells (116 –119). Nev-      in concert with mature resident stromal      glial cell (139 –141). However, mesen-
ertheless, infarct remodeling and exer-       cells (47). Angiogenesis occurs naturally    chymal stem cells, which are grown on
cise capacity showed improvement after        but is often insufficient to allow for       soft matrices, have also been found to
bone marrow stem cell therapy for the         wound healing. Vasculogenesis, con-          give rise to neuronal cells. This finding
first 4 – 6 months, with patients with the    versely, is defined as de novo phenom-       has caused a paradigm shift from a
largest infarcts benefiting the most (120).   ena initiated by progenitor stem cells       dogma of cell lineage restriction with
    Embryonic stem cells, which can be        giving rise to a surrogate vascular net-     regard to further cell differentiation to
transdifferentiated into cardiomyo-           work (47). Although it was previously        one of potential crossing of individual
cytes in vitro, have been successfully        believed that vasculogenesis only occurs     cell populations to other germ layers.
used to restore atrioventricular con-         during embryonic development, endo-          More important, bone marrow– derived
duction in pigs and guinea pigs with          thelial progenitor cells have subse-         stem cells have created neurons in vivo
atrioventricular blocks (121,122). Al-        quently been found in peripheral blood       (142,143). Consequently, granulocyte
though evaluation for the optimal             of adults and harvested from peripheral      colony stimulating factor has been used
stem cell delivery route is ongoing,          blood or bone marrow for performance         to stimulate the release of endogenous
current concepts favor combined tis-          of various clinical trials with the intent   bone marrow stem cells for angio- and
sue cell intramyocardial stem cell in-        to use endothelial progenitor cells for      neurogenesis and, in addition, reduces
jection over single cell line suspension      the treatment of critical limb ischemia      neuronal apoptosis and stimulates neu-
intracoronary injection because the lat-      (47). The first report in 2002 (129) dem-    ral progenitor cells in the treatment of
ter has been associated with the occur-       onstrated the safety and efficacy of in-     acute stroke (144,145). Engraftment effi-
rence of microinfarctions (123).              tramuscular injection of bone marrow         ciency comparisons and potential com-
                                              cells in patients with chronic limb isch-    plementary effects of catheter-directed
Peripheral Arterial Disease                   emia and significantly improved ankle-       selective delivery of exogenous stem
                                              brachial pressure indexes, transcutane-      cells and endogenous stem cell mobili-
   Peripheral arterial disease of all         ous oxygen pressures, and pain-free          zation would be one ideal realm of re-
stages has an estimated prevalence of         walking times while reducing rest pain       search for the neurointerventionalist.
4.2%–35% (124). It progresses to criti-       at 4- and 24-week follow-up. Multiple            Stem cell therapy has been applied to
cal limb ischemia in 4.3%–9.6% of             following studies confirmed these initial    a variety of neurologic disorders and
cases, conveying quality of life indexes      results, with two studies also demon-        entities that may be categorized as
similar to those of terminal cancer pa-       strating improvement of endothelial          chronic degenerative (eg, Parkinson and
tients and the eventual undesirable           function and increased blood perfusion       Alzheimer disease), acute traumatic (eg,
outcome of amputation (124,125). Dia-         as assessed with 99mTc tetrofosmin per-      cord injury), metabolic, and autoim-
betic patients are at highest risk for the    fusion scintigraphy (130 –137). Granulo-     mune (eg, MS) disorders. Stem cell ther-
development of gangrene and neces-            cyte stimulating factor, which is known      apy of neurologic disorders will be ex-
sity of amputation (126). About 40% of        to mobilize hematopoetic and endothe-        emplified by a discussion of stem cell
patients with critical limb ischemia are      lial progenitor cells from the bone mar-     treatment of stroke, Parkinson disease,
not candidates for revascularization          row into the circulation, has been used      and MS (21,146 –148).
procedures, performance of amputa-            to stimulate bone marrow– derived                Stroke.—Bone marrow– derived—
tion portends an even worse prognosis         stem cells before harvesting and thera-      specifically mesenchymal stem cells—
where it appears indicated, and no ef-        peutic administration of these cells and     and human umbilical cord blood stem
fective pharmacologic therapy is avail-       likewise found improvement in critical       cells have been tested for potential ther-
able for these patients (127,128). At the     limb ischemia and peripheral vascular        apeutic applications in stroke. Multiple
same time, bone marrow– derived en-           parameters with additional improve-          studies have demonstrated functional
dothelial progenitor cells have shown         ment of glucose metabolism in one            outcome improvement after intrave-
promise in providing neovasculariza-          study (138). Currently reported results      nous, intracerebral, or intraarterial stem
tion and have been found to contrib-          for stem cell utilization for peripheral     cell application in animal experiments
ute to wound healing (46).                    vascular disease are limited by the lack     even 4 weeks after the ischemic insult
   Vascular cells develop from embry-         of randomized, controlled studies as         (146 –148). Notably, a neurorestorative
onic stem cells through mesodermal dif-       well as longer-term clinical follow-up.      effect through stem cell administration
ferentiation into cardiovascular progen-      Although the vast majority of investiga-     is accomplished by the promotion of an-
itor cells or hemangioblasts (11).            tors have opted for the intramuscular        giogenesis, neurogenesis, and synapto-
Volume 20     Number 8                                                                                     Nikolic et al       •   1007


genesis rather than transdifferentiation      for Parkinson disease have generated         has been intravenous and intraventricular
of stem cells to fully functional neuronal    inconsistent results (156 –158). Lessons     administration of neural progenitor cells
cells (149). The angiogenetic effect of       learned from previous research in this       (24). These cells have been found to be
stem cells is not surprising because stem     area include the fact that the use of        therapeutic through anti-inflammatory
cells have been identified as potent pro-     embryonic stem cells for this applica-       effects in a pro-inflammatory environ-
ducers of vascular endothelial growth         tion may be inefficient and entail the       ment and neuroregenerative effective-
factor, a positive regulator and pro-         risk of teratoma formation, an unwar-        ness in a neurodegenerative environ-
moter of vessel formation (150,151).          ranted ability of embryonic stem cells       ment, consistent with effective targeting
There has also been one clinical trial in     that has also been observed in other         of MS in its acute and chronic stages,
which the study group received mesen-         anatomic areas and seems to be site-         respectively (23,163). The utility of stem
chymal stem cells intravenously after         dependent (159). Consequently, mes-          cells in the treatment of MS underscores
middle cerebral artery infarction and         enchymal cells that had been cultured        and exemplifies the potential immuno-
showed improved functional recovery           to assume characteristics of dopami-         suppressive effect of stem cells in auto-
compared to a control group during            nergic neurons have been used more           immune diseases.
1-year follow-up (152). Human umbili-         successfully for Parkinson disease
cal cord blood cells via the intravenous      therapy in one study (160).                  Cell-based Therapy for the
as well as intrastriatal (directly into the      A very interesting and more elegant       Treatment of Diabetes Mellitus
globus pallidus/putamen) delivery             approach is stem cell–mediated delivery
route have also been used for stroke          of glial cell line– derived neurotrophic         The treatment of diabetes mellitus
treatment. Although results have not          factor, a protein that promotes dopami-      that is refractory to medical therapy
been entirely consistent, successes have      nergic neuron preservation and differ-       has been a clinical challenge and re-
been attributed to the immunosuppres-         entiation. This type of stem cell use as a   sulted in the emergence of pancreas
sive as well as angiogenetic effects of the   vehicle for gene therapy has resulted in     transplantation as a therapeutic op-
administered cells (61,153–155). As in        glial cell line– derived neurotrophic fac-   tion. Pancreas transplantation, how-
other areas of stem cell treatment, the       tor expression in vivo and led to pro-       ever, is associated with limited donor
timing of cell administration is likely       longed neuron survival as well as func-      supply and substantial morbidity and
quintessential because the later stage of     tional improvement (161). Notably,           costs and requires lifelong immuno-
stroke evolution results in an intraaxial     intraarterial catheter-directed adminis-     suppression. Cell-based therapy, con-
cavity that is poorly accessible for exog-    tration of adult stem cells into the pos-    versely, is more elegant, more cost ef-
enous cells. Although an approach of          terior circulation has recently been pre-    fective, and less invasive. The initial
intracavity stem cell transplantation         sented as a beneficial and efficient way     approach of cell-based therapy en-
via a biodegradable scaffold has              of improving symptoms in patients            tailed harvesting of islet cells from
been developed, stem cell delivery to         with Parkinson disease in a clinical trial   brain-dead donors, a strategy that is
the infarcted territory is likely more        encompassing 47 patients (162). In sum-      still characterized by a limited donor
effective if performed before the late        mary, currently available research sug-      supply. Among the various target areas
stage of infarct evolution. Neverthe-         gest that stem cell– based therapy of Par-   and delivery routes of stem cell injection
less, on the basis of current knowl-          kinson disease is most successful if cells   (percutaneous intrasplenic, subcapsular
edge, stem cell therapy has the po-           are used that have undergone prediffer-      renal, intra-omental, subcutaneous, and
tential to expand the current 3– 6            entiation in vitro and possess dopami-       into the celiac artery), intraportal ve-
hour postevent treatment window               nergic properties, an approach that may      nous delivery has emerged as the tech-
(for thrombolytic therapy) to several         also be most useful in many other ana-       nically most feasible, least complicated,
weeks. Although some of the initial           tomic areas. The use of genetically mod-     and most efficient way of islet cell deliv-
experimental results for stroke treat-        ified stem cells that express glial cell     ery even though occurrence of bleeding
ment with stem cells are promising,           line– derived neurotrophic factor as ve-     complications as well as portal vein
the notion that stem cells may restore        hicles for gene therapy is likewise prom-    thrombosis that is apparently related to
complex functional anatomy seems              ising and has thus far been free of asso-    intraprocedural increases in portal ve-
to be an overreaching expectation at          ciated tumor formation (161).                nous pressure have been described
the current time. Rather, stem cell               MS.—MS is an inflammatory auto-          (59,164). The investigative team from
therapy may be a functional recovery          immune disease that may be charac-           the University of Alberta must be cred-
facilitator through angiogenesis,             terized by a progressive or relapsing        ited with pioneering work of successful
neurogenesis, and synaptogenesis              course. Autologous bone marrow– de-          portal vein infusion of islet cells in pa-
promotion.                                    rived stem cells have also been found        tients with medically refractory type I
   Parkinson disease.—Parkinson dis-          most suitable for stem cell– based ther-     diabetes mellitus, which effectively con-
ease was once believed to be an ideal         apy for this entity as well and have         trolled blood glucose levels for 1 year
target for stem cell therapy because it       been most successful at an early stage       before disease recurrence (59).
requires replacement of only one dis-         of the disease and if performed as non-          Stem cell– based therapeutic investi-
tinct cell population in the substantia       myeloablative therapy. The rationale         gations have been conducted in animal
nigra, unlike in the therapy of stroke,       for stem cell therapy for this disease is    experiments but have been compounded
which is characterized by the territo-        to create an immunologically “naïve”         by the lack of a clearly identifiable type of
rial demise of numerous different             state through autologous hematopo-           pancreatic stem cell. Embryonic stem cells
types of cell populations. However,           etic stem cells (22). A second approach      have been transformed into cells with ␤
stem cell– based treatment attempts           that has generated promising results         cell properties, although controversy sur-
1008   •   Primer on Stem Cell Therapy                                                                               August 2009      JVIR



rounds the issue as to whether these           izing dysfunctional or malignant tissue           3. Takahashi K, Tanabe K, Ohnuki M, et
cells produce or simply absorb insulin         by means of RF ablation. Periablational              al. Induction of pluripotent stem cells
(165–167). Nevertheless, transplanted          hyperemia and/or ingrowing granula-                  from adult human fibroblasts by de-
embryonic stem cells have been success-        tion tissue may then provide a vascular              fined factors. Cell 2007; 131:861– 872.
fully used to improve or cure diabetes in      environment that allows for highly effi-          4. Yu J, Vodyanik MA, Smuga-Otto
                                                                                                    K, et al. Induced pluripotent stem
rodents (43– 45). The ability of hemato-       cient stem cell trafficking to the selected
                                                                                                    cell lines derived from human so-
poetic and bone marrow– derived stem           target area and subsequent stem cell en-             matic cells. Science 2007; 318:1917–
cells to differentiate into functional islet   graftment. In addition, the role of devas-           1920.
cells has also been accomplished in ro-        cularization of dysfunctional tissue              5. Samavedi V, Sacher RA, Efiom-Ekaha
dents (168,169). Subcapsular renal trans-      through transarterial catheter emboliza-             D, Patel AG, Kuku A, Ladapo A. He-
plantation of bone marrow– derived             tion could be explored. Both techniques              matopoietic stem cell transplantation.
cells that had been differentiated toward      (ie, RF ablation and transarterial cathe-            Available at http://www.emedicine.
insulin-expressing cells in vitro resulted     ter embolization) may be followed by                 com/med/ byname/Hematopoietic-
in glucose level correction in rodents,        subsequent targeted transarterial cell               Stem-Cell-Transplantation.htm. Ac-
which was reversed after removal of the        delivery to improve stem cell trafficking            cessed June 25, 2009.
                                               efficiency when compared to peripheral            6. Farquhar C, Marjoribanks J, Basser R,
grafted kidney (170,171).
                                                                                                    Lethaby A. High dose chemother-
   Like in other organs, in vitro differ-      intravenous cell administration.                     apy and autologous bone marrow or
entiation of toti- or pluripotent cells            The imaging radiologist should                   stem cell transplantation versus con-
into endocrine pancreatic cells before         continue to develop and refine imag-                 ventional chemotherapy for women
transplantation seems most efficient.          ing techniques that allow for stem cell              with early poor prognosis breast can-
The intraportalvenous delivery route           tracking (eg, by means of SPIO label-                cer. Cochrane Database Syst Rev 2005;
appears to best combine engraftment            ing of stem cells) and take an active                20:CD003139.
efficiency with low complication rates         role in exploring occurrences and ex-             7. Farquhar CM, Marjoribanks J, Lethaby
and technical feasibility.                     tent of stem cell engraftment, migra-                A, Basser R. High dose chemotherapy
                                               tions, and stem cell effect on organ                 for poor prognosis breast cancer: sys-
                                               (system) functionality based on imag-                tematic review and meta-analysis. Can-
CONCLUSIONS AND FUTURE                                                                              cer Treat Rev 2007; 33:325–337.
PROSPECTS                                      ing.                                              8. Takahashi M, Nakamura T, Toba T,
                                                   In pursuit of these objectives, both             Kajiwara N, Kato H, Shimizu Y.
    For many years, stem cell therapy          the diagnostic radiologist and the in-               Transplantation of endothelial pro-
has been accepted as the first- or front-      terventional radiologist will be firmly              genitor cells into the lung to alleviate
line therapy for disease entities such as      integrated in this promising and still-              pulmonary hypertension in dogs. Tis-
blood dyscrasias or certain autoim-            developing field of medicine and be-                 sue Eng 2004; 10:771–779.
mune diseases. In other anatomic ar-           come valuable partners for basic sci-             9. Lagasse E, Connors H, Al-Dhalimy M,
eas, the use of stem cells for treatment       ence researchers and clinicians alike.               et al. Purified hematopoietic stem
is at various stages of research and                                                                cells can differentiate into hepatocytes
clinical application but research activity                                                          in vivo. Natl Med 2000; 6:1229 –1234.
                                               Acknowledgments: Boris Nikolic, MD,              10. Yamamoto H, Quinn G, Asari A, et al.
is rich in all, progress is rapid, and im-     authored the first draft of this document            Differentiation of embryonic stem
plementation into clinical routine will        and served as topic leader during the sub-           cells into hepatocytes: biological func-
likely eventually occur in most—if not         sequent revisions of the draft. Michael D.           tions and therapeutic application.
all—areas of current research. Conse-          Kuo, MD, is Chair of the Emerging Tech-              Hepatology 2003; 37:983–993.
quently, any review about stem cell            nologies Subcommittee. Steven F Mill-            11. Bai H, Wang ZZ. Directing human
therapy tends to be outdated quickly.          ward, MD, is Chair of the Technology As-             embryonic stem cells to generate vas-
Nevertheless, distinct trends are identi-      sessment Committee. John F. Cardella,                cular progenitor cells. Gene Ther
fiable at the current time that can be         MD, is Councilor of the SIR Standards Di-            2008; 15:89 –95.
                                               vision. Other members of the Emerging            12. Fiegel HC, Lioznov MV, Cortes-De-
exploited for the future and may define        Technologies Subcommittee and SIR who
the role of the interventional and diag-                                                            ricks L, et al. Liver-specific gene ex-
                                               participated in the development of this              pression in cultured human hemato-
nostic radiologist in the area of stem cell    clinical practice guideline are (listed alpha-       poietic stem cells. Stem Cells 2003; 21:
therapy. For instance, the interventional      betically): John “Fritz”Angle, MD, Danny             98 –104.
radiologist should advance knowledge of        Chan, MD, B. Janne D’Othee, MD, Maxim            13. Heine W, Conant K, Griffin JW,
stem cell engraftment kinetics and opti-       Itkin, MD, Donald L. Miller, MD, Darren              Hoke A. Transplanted neural stem
mize administration timing and delivery        Postoak, MD, Tarun Sabharwal, MD, Timo-              cells promote axonal regeneration
route through participation in—or pri-         thy L. Swan, MD, and Patricia E. Thorpe,             through chronically denervated pe-
mary investigation of—various research         MD.                                                  ripheral nerves. Exp Neurol 2004; 189:
projects of tissue engineering. In vitro                                                            231–240.
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