Advances in Stem Cell-Based Therapy for Hair Loss - CellR4

CellR4 2020; 8: e2894

Advances in Stem Cell-Based Therapy for Hair Loss
A. Egger, M. Tomic-Canic, A. Tosti
Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

Corresponding Author: Andjela Egger, BS; e-mail: axn404@med.miami.edu

   Keywords: Hair loss, Alopecia, Stem cell-based therapy,          more detailed description of the latest clinical
Transplant, Conditioned medium, Exosome, Hair regrowth,             studies concerning stem cell-based therapies in
Hair regeneration.                                                  hair loss.

Abstract
Hair loss is a quite common condition observed                      Introduction
in both men and women. Pattern hair loss also                       Hair loss, particularly, pattern hair loss (PHL) as its
known as androgenetic alopecia is the most com-                     most common form, occurs quite commonly in both
mon form of hair loss that is thought to affect                     women and men, and often leads to a significant
up to 80% of Cauca-sian men and up to 40%                           decrease in quality of life1. It is believed that over
of Caucasian women by age of 70, and it can                         80% of Caucasian men and up to 42% of Caucasian
have quite devastating consequenc-es on one’s                       women at the age of 70 are affected by male pattern
well-being, including lower self-esteem, depres-                    hair loss/androgenetic alopecia (MPHL/AGA) and
sion and lower quality of life. To date there have                  female pattern hair loss (FPHL), respectively1. Hair
only been 2 FDA approved medications, min-                          is considered a major feature of beauty and esthetic
oxidil and finasteride, but their effects are often                 appearance; hence hair loss has a major impact on
unsat-isfactory and temporary, in addition to                       one’s self-perception, self-esteem, and can lead to
having various adverse effects. Stem cell-based                     depression and other mood disorders2. Furthermore,
therapies have re-cently received lots of attention                 some postulate early onset of AGA to be associated
as potential novel treatments that focus on reac-                   with a heightened risk of development of myocardial
tivating hair follicle stem cells and in this way                   infarction and metabolic syndrome3.
enhance hair follicle growth, regeneration and                          It is thought that the Wnt- β-catenin pathway
development. Stem cell-based therapy approach-                      plays a major role in pathogenesis of hair loss4. To
es include stem cell transplant, stem cell-derived                  date, there are only 2 FDA approved medications
conditioned medium and stem cell-derived exo-                       for treatment of hair loss, minoxidil (a vasodilator)
somes. A combination of following key words                         and finasteride (a selective inhibitor of the type II
was utilized for a PubMed search: cell-based                        and III isoforms of 5α-reductase). However, these
therapy, hair loss, alopecia, hair regrowth; ab-                    medications have been far from perfect; both have
stracts were screened and included based on the                     been associated with limited efficacy, duration of
content relevant to hair loss and stem-cell based                   effect, and several important side effects5, 6.
therapy. Preclinical research utilizing these ap-                       PHL is a form of non-scarring alopecia. PHL is
proaches has blossomed in the past decade along                     characterized by defects in and loss of hair progen-
with a more limited number of clinical studies,                     itor cells, while hair follicle stem cells (HFSCs) re-
overall demonstrating very promising find-ings.                     main viable. This notion in particular makes PHL a
However, stem cell-based therapies for hair loss                    reversible condition7,8, and current and novel treat-
are still at their infancy and more robust clini-                   ment modalities attempt to utilize the existent vi-
cal studies are needed to better evaluate their                     ability and responsiveness of HFSCs as to reverse
mechanisms of action, efficacy, safety, benefits                    hair loss pathology and promote hair growth. Pro-
and limitations. In this review, we provide the                     viding adequate signals and environment to reacti-
resources to the latest preclinical studies and a                   vate HFSCs and regrow a hair follicle is of partic-

1

2     A. Egger, M. Tomic-Canic, A. Tosti

ular interest to the hair regeneration scientific and       Rigenera® is a technology that obtains autolo-
clinical community. In the past decade, hair regen-     gous mature stem cells from biopsies of a patient
eration research has plummeted, including the dis-      using a preparation system for mechanical disin-
coveries regarding stem-cell based therapies lead-      tegration and filtering of solid tissues. In a study
ing to many preclinical and some clinical studies       the cell suspension was injected into the scalp of 11
with encouraging outcomes. Stem-cell transplant,        patients affected by AGA. 23 weeks post-treatment
stem cell-derived conditioned medium (CM) and           there was a 29%±5% increase in hair density in the
stem cell-derived exosomes have recently gained         scalp area receiving treatment as compared to the
a lot of attention as potential new agents to mod-      area receiving placebo15. Gentile et al15 suggested
ify and enhance the signaling pathways that could       that bulge-derived HFSCs can be isolated with this
induce HFSC reactivation, hair cycle and hair fol-      newly discovered method to avoid the challenges
licle regeneration. In this review, we will provide     concerning cell culturing and more importantly
resources to the preclinical studies, but our major     that they have the ability to enhance hair density in
focus will be on the latest clinical research as it     patients with AGA.
relates to stem-cell based therapies, hair loss, and        Multipotent stem cells arising from the adipose
hair regeneration potential.                            tissue – the adipose-derived stromal vascular cells
                                                        (ADSVCs) or adipose-derived regenerative cells
Discussion                                              (ADRCs) refer to the stromal vascular fraction-de-
As briefly mentioned previously, stem-cell based        rived freshly used primary multipotent stem cells.
therapies include three distinct prospective mech-      When these cells are cultured, they attain additional
anisms: transplantation of multipotent stem cells       features and become a population of mesenchymal
from different sources, application of stem cell-de-    stem cells (MSCs) which are referred to as adi-
rived CM and application of stem-cell derived           pose-derived stem cells (ADSCs)16,17. Anderi et al16
exosomes9. Herein, we will address each of them         studied ADSVCs in a total of 20 patients suffering
individually by discussing current clinical studies,    from AA16. There was a statistically significant im-
their results, respective benefits and limitations.     provement of hair thickness especially 6 months
    Transplantation of multipotent stem cells has       post-treatment. Only 1 out of 20 patients did not
become a well-accepted treatment option for hair        demonstrate any increase in hair diameter. Further-
loss (especially AGA). The sources of multipo-          more, there was a statistically significant increase
tent stem cells with regenerative potentials of hair    in hair density 3 and 6 months post-treatment; 18
follicles in the skin include adipose tissue10, bone    out of 20 patients demonstrated improvement while
marrow11, hair follicles from unaffected areas12, and   only 2 out of 20 patients did not show any increase
umbilical cord blood13.                                 in hair density. Lastly, there was also a statistically
    Owczarczyk-Saczonek et al8 provide a thorough       significant decrease in hair-pull test results 3 and 6
review of pre-clinical discoveries of promising         months post-treatment; only 2 out of 20 patients did
results and benefits of stem-cell based transplant      not demonstrate any decrease in hair-pull test scores.
therapies. Results of clinical studies are further      Anderi et al16 suggested autologous ADSVCs graft
discussed below.                                        to be safe and effective treatment modality for AA.
    Elmaadawi et al14 studied the safety and efficacy       Zanzottera et al10 utilized the Rigenera® de-
of the autologous bone marrow-derived mononucle-        vice to prepare autologous ADMSCs obtained
ar cells (BMMCs) including stem cells in compari-       during hair transplant procedure. The suspension
son to follicular stem cells (FSCs) obtained from the   was then applied to the scalp areas undergoing
unaffected scalp areas in 20 patients with alopecia     hair transplant in 3 patients suffering from AGA.
areata (AA) and 20 patients with AGA. All patients      Monthly follow up revealed a more rapid healing
underwent one treatment session with autologous         of transplant-induced wounds. Furthermore, there
stem cells (BMMCs or FSCs) that were inject-            was a continuous improvement in hair growth and
ed intradermally. Evaluation by immunostaining          a shorter telogen phase two months post-treatment.
and digital dermoscopy 6 months post-treatment              Another study found benefit of primary pluripo-
demonstrated significant improvement of both            tent ADRCs in enhancing hair growth. Particularly,
conditions with no significant difference between       addition of stromal vascular fraction-derived stem
treatment groups and no adverse events.                 cells to the adipose tissue in a transplant procedure

Stem Cell Therapy for Hair Loss   3

involving 6 patients suffering from male or female        additional benefits. For instance, the donor-recipi-
PHL demonstrated a statistically significant 23%          ent match that is normally required in a cell-based
increase in mean hair count compared to 7.5% in-          type of treatment is surpassed with CM because it
crease in patients treated with adipose tissue alone17.   represents a cell-free medium26. Additionally, there
   The dermal papilla (DP) region is an important         appears to be less risk of tumor development as well
area of the hair follicle that contains MSCs which        as benefits of easier preparation and lower cost27, 28.
participate in inducing hair growth and controlling       Although stem cell-derived CM-based therapy is at
hair cycle. DP cells are surrounded by dermal             its early beginnings, many preclinical9 and several
sheath cup (DSC) cells which are essential for DP         clinical studies have shown encouraging results.
cell regeneration and proliferation and therefore         The clinical studies will be discussed below.
hair growth, as well18. It is proposed that circulat-         Fukuoka et al29 evaluated efficacy and safety of
ing androgens deregulate DP cell-derived signaling        ADSC-CM in 25 patients (12 women and 13 men)
leading to inhibition of canonical Wnt-β-catenin          diagnosed with female or male PHL; 1 male patient
pathway and hair loss in AGA4. Besides DP cells,          received a diagnosis of both AGA and AA. In this
the multipotent stem cells from the bulge region are      study, ADSCs were pretreated under hypoxic con-
also thought to depend on DSC cells19. In a study         ditions that were previously shown to have the abil-
by Tsuboi et al20, 50 male and 15 female patients         ity to induce secretion of various growth factors
received a single injection treatment of autologous       and cytokines with potential benefits for hair re-
DSC cells at concentrations 7.5 x 106, 1.5 x 106, or      growth as compared to normoxic ADSCs29,30. The
3.0 x 105 DSC cells or a placebo in 4 randomized          ADSC-derived secretome is composed of hepato-
distinctive scalp regions and were followed-up at         cyte growth factor, vascular endothelial growth
3, 6, 9 and 12 months post-treatment. There was           factor, keratinocyte growth factor and platelet-de-
a significant increase in total hair density and cu-      rived growth factor29. This medium was applied
mulative hair diameter at the 3.0 x 105 DSC cell          every 3-5 weeks by utilizing nappage and papule
injection location 6 and 9 months post-treatment.         injection methods. All patients demonstrated a
These results suggested that autologous DSC cell          statically significant improvement in hair growth;
injection at minimal concentration is a potential         4 treatment sessions over a 3-4-month-period re-
safe and useful additional modality for treatment         sulted in best results29.
of PHL in both males and females.                             In another study of the same group on 22 pa-
   A new focus is being placed on stem-cell secret-       tients (11 men and 11 women) with alopecia re-
ed bioactive molecules such as growth factors, cy-        ceived ADSC-CM injections every 3-5 weeks for a
tokines, chemokines, and others, as potential key         total of 6 sessions. 10 patients (8 men and 2 wom-
regulators of hair follicle cycle and regeneration9.      en) were also part of a half-side comparison study.
Particularly, it is thought that up to 80% of regen-      Trichogram evaluations before and after treatment
erative properties of transplanted stem cells come        demonstrated a statistically significant increase in
from paracrine factor signaling21, 22. Stem cells se-     hair numbers in both genders. In the half-side com-
crete such factors including nucleic acids, extra-        parison study, the side receiving treatment exhibit-
cellular vesicles (exosomes included) and proteins,       ed a significant increase in hair numbers compared
thus inducing paracrine signaling23, 24. These fac-       to the side of placebo31. Adverse events included
tors are components of a secretome. In other words,       post-procedural pain which negatively affected pa-
secretome represents a set of signaling molecules         tient compliance.
including nucleic acids, extracellular vesicles, and          ADSC-CM was also evaluated in 27 female pa-
proteins secreted by stem cells. When a cultured          tients suffering from FPHL. This group utilized a
stem cell-derived secretome is present in a nutri-        microneedle roller to apply ADSC-CM weekly for
ent-rich medium it is referred to as a stem cell-de-      12 consecutive weeks. Phototrichographic analysis
rived “conditioned medium” (CM)25.                        revealed a statistically significant increase in both
   Several studies focusing specifically on the           hair density and hair thickness, and no adverse
ability of the extracellular matrix (EM) to induce        events (including pain)32.
hair regeneration are available and overall their re-         Narita et al33 evaluated efficacy of ADSC-CM
sults are promising9. Moreover, in comparison to          in a total of 40 patients (21 men and 19 women)
other modalities, stem cell-derived CM provides           diagnosed with alopecia. Patients underwent AD-

4     A. Egger, M. Tomic-Canic, A. Tosti

SC-CM intradermal injections monthly for a total           plant, CM and exosome therapies demonstrate
of 6 months and had follow-up evaluations before           preclinical and some clinical success, each one
and at 2, 4 and 6 months post-treatment. There was         of them has its own limitations that will need to
a significant increase in hair density and anagen          be overcome. Stem cell transplant is a costly pro-
hair rate in this study, as well as, dermal echoge-        cedure, and it also raises concerns for tumorige-
nicity and dermal thickness of the treated scalp33         nicity24. While CM and exosomes may be more
    Undoubtedly, CM demonstrates potential as a            affordable26 and safe in terms of tumor devel-
future hair regrowth therapy; however, like any            opment27, 28 they both pose some problems. The
treatment modality it poses certain limitations.           cell-free nature of CM provides a safer and more
Particularly, the type and level of factors present in     immunocompatible environment, but makes iso-
a stem cell-derived CM can be highly variable, and         lating a composition-consistent CM challenging26.
standardization of its preparation will be of utmost       Similarly, there are currently no standard effective
importance to improve its clinical use and results22.      isolation methods for exosomes39. While results
Additionally, fast turnover and depletion of CM            are certainly hopeful, larger and more robust dou-
factors in vivo may necessitate large quantities and       ble blind controlled clinical trials are needed to
frequent application34,35. We will now briefly dis-        further assess the exact mechanisms, therapeutic
cuss one particular component of CM that is con-           potential and safety of stem-cell based approaches
sidered an additional alternative stem-cell based          to hair loss management.
therapeutic approach: the exosome.
    Exosomes are extracellular vesicles of the small-      Funding:
est size, that act as cell-to-cell transporters and mes-   Our work is supported by the National Institute of Health grants
sengers by carrying signaling molecules including          (U01DK119085, R01NR015649 and R01AR073614 to M. T.-C.)
transcription factors, cytokines, and RNA22,36,37.         and research funds from the Frost Department of Dermatology
Exosomes have been demonstrated as important               and Cutane-ous Surgery.
modulators of paracrine signaling, and particularly,
DP cell-derived exosomes could be of major impor-          Conflict of Interest:
tance for hair follicle regeneration38. Many of the        The authors declare that they have no conflict of interest to
preclinical studies show favorable outcomes; how-          disclose.
ever, there are currently no clinical studies employ-
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