Stem Cell Therapy: A Primer for Interventionalists and Imagers
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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
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 significant1002 • 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 radiometalVolume 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 by1004 • 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 differentiationVolume 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 marrow1006 • 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-
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In pursuit of these objectives, both Kajiwara N, Kato H, Shimizu Y.
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has been accepted as the first- or front- terventional radiologist will be firmly genitor cells into the lung to alleviate
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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
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