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September 22.
Published in final edited form as:
CellR4 Repair Replace Regen Reprogram. 2020 ; 8: .

Advances in Stem Cell-Based Therapy for Hair Loss

Andjela Egger1, Marjana Tomic-Canic1, Antonella Tosti1
1Dr.
Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller
School of Medicine, Miami, Florida, U.S.A.

Abstract
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OBJECTIVE: Hair loss is a quite common condition observed in both men and women. Pattern
hair loss also known as androgenetic alopecia is the most common form of hair loss that is
thought to affect up to 80% of Caucasian men and up to 40% of Caucasian women by age
of 70, and it can have quite devastating consequences on one’s well-being, including lower
self-esteem, depression and lower quality of life. To date there have only been 2 FDA approved
medications, minoxidil and finasteride, but their effects are often unsatisfactory and temporary,
in addition to having various adverse effects. Stem cell-based therapies have recently received
lots of attention as potential novel treatments that focus on reactivating hair follicle stem cells
and in this way enhance hair follicle growth, regeneration and development. Stem cell-based
therapy approaches include stem cell transplant, stem cell-derived conditioned medium and stem
cell-derived exosomes.

MATERIALS AND METHODS: A combination of following key words was utilized for a
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PubMed search: cell-based therapy, hair loss, alopecia, hair regrowth; abstracts were screened and
included based on the content relevant to hair loss and stem-cell based therapy.

RESULTS: Preclinical research utilizing these approaches has blossomed in the past decade
along with a more limited number of clinical studies, overall demonstrating very promising
findings.

CONCLUSION: However, stem cell-based therapies for hair loss are still at their infancy and
more robust clinical studies are needed to better evaluate their mechanisms of action, efficacy,
safety, benefits and limitations. In this review, we provide the resources to the latest preclinical
studies and a more detailed description of the latest clinical studies concerning stem cell-based
therapies in hair loss.
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Keywords
hair loss; alopecia; stem cell-based therapy; transplant; conditioned medium; exosome; hair
regrowth; hair regeneration

Corresponding author: Andjela Egger, B.S., Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University
of Miami Miller School of Medicine, 1600 NW 10th Avenue, RMSB 6056, Miami, FL 33136, Phone: 425 394 3603,
axn404@med.miami.edu.
Conflicts of Interest: The authors declare that they have no conflict of interest to disclose.
 Egger et al. Page 2

Introduction:
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Hair loss, particularly, pattern hair loss (PHL) as its most common form, occurs quite
commonly in both women and men, and often leads to a significant decrease in quality of
life1. It is believed that over 80% of Caucasian men and up to 42% of Caucasian women
at the age of 70 are affected by male pattern hair loss/androgenetic alopecia (MPHL/AGA)
and female pattern hair loss (FPHL), respectively1. Hair is considered a major feature of
beauty and esthetic appearance; hence hair loss has a major impact on one’s self-perception,
self-esteem, and can lead to depression and other mood disorders2. Furthermore, some
postulate early onset of AGA to be associated with a heightened risk of development of
myocardial infarction and metabolic syndrome3.

It is thought that the Wnt- β-catenin pathway plays a major role in pathogenesis of hair
loss.4 To date, there are only 2 FDA approved medications for treatment of hair loss,
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minoxidil (a vasodilator) and finasteride (a selective inhibitor of the type II and III isoforms
of 5α-reductase). However, these medications have been far from perfect; both have been
associated with limited efficacy, duration of effect, and several important side effects5, 6.

PHL is a form of non-scarring alopecia. PHL is characterized by defects in and loss of

hair progenitor cells, while hair follicle stem cells (HFSCs) remain viable. This notion in
particular makes PHL a reversible condition7, 8, and current and novel treatment modalities
attempt to utilize the existent viability and responsiveness of HFSCs as to reverse hair
loss pathology and promote hair growth. Providing adequate signals and environment to
reactivate HFSCs and regrow a hair follicle is of particular interest to the hair regeneration
scientific and clinical community. In the past decade, hair regeneration research has
plummeted, including the discoveries regarding stem-cell based therapies leading to many
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preclinical and some clinical studies with encouraging outcomes. Stem-cell transplant, stem
cell-derived conditioned medium (CM) and stem cell-derived exosomes have recently gained
a lot of attention as potential new agents to modify and enhance the signaling pathways that
could induce HFSC reactivation, hair cycle and hair follicle regeneration. In this review, we
will provide resources to the preclinical studies, but our major focus will be on the latest
clinical research as it relates to stem-cell based therapies, hair loss, and hair regeneration
potential.

Discussion:
As briefly mentioned previously, stem-cell based therapies include three distinct prospective
mechanisms: transplantation of multipotent stem cells from different sources, application
of stem cell-derived CM and application of stem-cell derived exosomes9. Herein, we
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will address each of them individually by discussing current clinical studies, their results,
respective benefits and limitations.

Transplantation of multipotent stem cells has become a well-accepted treatment option

for hair loss (especially AGA). The sources of multipotent stem cells with regenerative
potentials of hair follicles in the skin include adipose tissue10, bone marrow11, hair follicles
from unaffected areas12, and umbilical cord blood13.

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Owczarczyk-Saczonek et al8 provide a thorough review of pre-clinical discoveries of

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promising results and benefits of stem-cell based transplant therapies. Results of clinical
studies are further discussed below.

Elmaadawi et al14 studied the safety and efficacy of the autologous bone marrow-derived
mononuclear cells (BMMCs) including stem cells in comparison to follicular stem cells
(FSCs) obtained from the unaffected scalp areas in 20 patients with alopecia areata (AA) and
20 patients with AGA. All patients underwent one treatment session with autologous stem
cells (BMMCs or FSCs) that were injected intradermally. Evaluation by immunostaining and
digital dermoscopy 6 months post-treatment demonstrated significant improvement of both
conditions with no significant difference between treatment groups and no adverse events.

Rigenera® is a technology that obtains autologous mature stem cells from biopsies of
a patient using a preparation system for mechanical disintegration and filtering of solid
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tissues. In a study the cell suspension was injected into the scalp of 11 patients affected
by AGA. 23 weeks post-treatment there was a 29%±5% increase in hair density in the
scalp area receiving treatment as compared to the area receiving placebo15. Gentile et al15
suggested that bulge-derived HFSCs can be isolated with this newly discovered method
to avoid the challenges concerning cell culturing and more importantly that they have the
ability to enhance hair density in patients with AGA.

Multipotent stem cells arising from the adipose tissue – the adipose-derived stromal vascular
cells (ADSVCs) or adipose-derived regenerative cells (ADRCs) refer to the stromal vascular
fraction-derived freshly used primary multipotent stem cells. When these cells are cultured,
they attain additional features and become a population of mesenchymal stem cells (MSCs)
which are referred to as adipose-derived stem cells (ADSCs)16, 17. Anderi et al16 studied
ADSVCs in a total of 20 patients suffering from AA16. There was a statistically significant
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improvement of hair thickness especially 6 months post-treatment. Only 1 out of 20 patients

did not demonstrate any increase in hair diameter. Furthermore, there was a statistically
significant increase in hair density 3 and 6 months post-treatment; 18 out of 20 patients
demonstrated improvement while only 2 out of 20 patients did not show any increase in hair
density. Lastly, there was also a statistically significant decrease in hair-pull test results 3
and 6 months post-treatment; only 2 out of 20 patients did not demonstrate any decrease
in hair-pull test scores. Anderi et al16 suggested autologous ADSVCs graft to be safe and
effective treatment modality for AA.

Zanzottera et al10 utilized the Rigenera® device to prepare autologous ADMSCs obtained
during hair transplant procedure. The suspension was then applied to the scalp areas
undergoing hair transplant in 3 patients suffering from AGA. Monthly follow up revealed
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a more rapid healing of transplant-induced wounds. Furthermore, there was a continuous

improvement in hair growth and a shorter telogen phase two months post-treatment.

Another study found benefit of primary pluripotent ADRCs in enhancing hair growth.
Particularly, addition of stromal vascular fraction-derived stem cells to the adipose tissue in
a transplant procedure involving 6 patients suffering from male or female PHL demonstrated

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a statistically significant 23% increase in mean hair count compared to 7.5% increase in
patients treated with adipose tissue alone17.
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The dermal papilla (DP) region is an important area of the hair follicle that contains
MSCs which participate in inducing hair growth and controlling hair cycle. DP cells are
surrounded by dermal sheath cup (DSC) cells which are essential for DP cell regeneration
and proliferation and therefore hair growth, as well18. It is proposed that circulating
androgens deregulate DP cell-derived signaling leading to inhibition of canonical Wnt-β-
catenin pathway and hair loss in AGA4. Besides DP cells, the multipotent stem cells from
the bulge region are also thought to depend on DSC cells19. In a study by Tsuboi et al20, 50
male and 15 female patients received a single injection treatment of autologous DSC cells at
concentrations 7.5 × 106, 1.5 × 106, or 3.0 × 105 DSC cells or a placebo in 4 randomized
distinctive scalp regions and were followed-up at 3, 6, 9 and 12 months post-treatment.
There was a significant increase in total hair density and cumulative hair diameter at the 3.0
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× 105 DSC cell injection location 6 and 9 months post-treatment. These results suggested
that autologous DSC cell injection at minimal concentration is a potential safe and useful
additional modality for treatment of PHL in both males and females.

A new focus is being placed on stem-cell secreted bioactive molecules such as growth
factors, cytokines, chemokines, and others, as potential key regulators of hair follicle cycle
and regeneration9. Particularly, it is thought that up to 80% of regenerative properties of
transplanted stem cells come from paracrine factor signaling21, 22. Stem cells secrete such
factors including nucleic acids, extracellular vesicles (exosomes included) and proteins,
thus inducing paracrine signaling23, 24. These factors are components of a secretome. In
other words, secretome represents a set of signaling molecules including nucleic acids,
extracellular vesicles, and proteins secreted by stem cells. When a cultured stem cell-derived
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secretome is present in a nutrient-rich medium it is referred to as a stem cell-derived

“conditioned medium” (CM)25.

Several studies focusing specifically on the ability of the extracellular matrix (EM) to
induce hair regeneration are available and overall their results are promising9. Moreover,
in comparison to other modalities, stem cell-derived CM provides additional benefits.
For instance, the donor-recipient match that is normally required in a cell-based type of
treatment is surpassed with CM because it represents a cell-free medium26. Additionally,
there appears to be less risk of tumor development as well as benefits of easier preparation
and lower cost27, 28. Although stem cell-derived CM-based therapy is at its early beginnings,
many preclinical9 and several clinical studies have shown encouraging results. The clinical
studies will be discussed below.
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Fukuoka et al29 evaluated efficacy and safety of ADSC-CM in 25 patients (12 women
and 13 men) diagnosed with female or male PHL; 1 male patient received a diagnosis of
both AGA and AA. In this study, ADSCs were pretreated under hypoxic conditions that
were previously shown to have the ability to induce secretion of various growth factors and
cytokines with potential benefits for hair regrowth as compared to normoxic ADSCs29, 30.
The ADSC-derived secretome is composed of hepatocyte growth factor, vascular endothelial
growth factor, keratinocyte growth factor and platelet-derived growth factor29. This medium

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was applied every 3–5 weeks by utilizing nappage and papule injection methods. All
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patients demonstrated a statically significant improvement in hair growth; 4 treatment

sessions over a 3–4-month-period resulted in best results29.

In another study of the same group on 22 patients (11 men and 11 women) with alopecia
received ADSC-CM injections every 3–5 weeks for a total of 6 sessions. 10 patients (8
men and 2 women) were also part of a half-side comparison study. Trichogram evaluations
before and after treatment demonstrated a statistically significant increase in hair numbers
in both genders. In the half-side comparison study, the side receiving treatment exhibited
a significant increase in hair numbers compared to the side of placebo31. Adverse events
included post-procedural pain which negatively affected patient compliance.

ADSC-CM was also evaluated in 27 female patients suffering from FPHL. This group
utilized a microneedle roller to apply ADSC-CM weekly for 12 consecutive weeks.
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Phototrichographic analysis revealed a statistically significant increase in both hair density

and hair thickness, and no adverse events (including pain)32.

Narita et al33 evaluated efficacy of ADSC-CM in a total of 40 patients (21 men and 19
women) diagnosed with alopecia33. Patients underwent ADSC-CM intradermal injections
monthly for a total of 6 months and had follow-up evaluations before and at 2, 4 and 6
months post-treatment. There was a significant increase in hair density and anagen hair rate
in this study, as well as, dermal echogenicity and dermal thickness of the treated scalp.

Undoubtedly, CM demonstrates potential as a future hair regrowth therapy; however, like

any treatment modality it poses certain limitations. Particularly, the type and level of
factors present in a stem cell-derived CM can be highly variable, and standardization of
its preparation will be of utmost importance to improve its clinical use and results22.
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Additionally, fast turnover and depletion of CM factors in vivo may necessitate large
quantities and frequent application34, 35. We will now briefly discuss one particular
component of CM that is considered an additional alternative stem-cell based therapeutic
approach: the exosome.

Exosomes are extracellular vesicles of the smallest size, that act as cell-to-cell transporters
and messengers by carrying signaling molecules including transcription factors, cytokines,
and RNA22, 36, 37. Exosomes have been demonstrated as important modulators of paracrine
signaling, and particularly, DP cell-derived exosomes could be of major importance for hair
follicle regeneration38. Many of the preclinical studies show favorable outcomes; however,
there are currently no clinical studies employing extracellular vesicle or exosome therapy for
hair growth9. More preclinical and new clinical studies are needed to further characterize
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exosomes as a novel regenerative treatment for hair loss.

More robust studies are encouraged for the other two stem cell-based therapy approaches:
the stem cell-based transplant and the stem cell-derived CM; several clinical trials
currently are underway (ClinicalTrials.gov Identifiers: NCT01673789, NCT02865421,
NCT03078686, NCT02849470, NCT03676400, NCT03662854, NCT 01501617). Several
aforementioned studies have been completed and are awaiting results.

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Conclusion:
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Novel discoveries revolving around stem-cell based therapies provide encouraging steps
towards developing more effective and successful hair loss treatments. Although these initial
steps towards such discoveries are hopeful, there is still a limited amount of clinical data
to fully support stem-cell based therapies. While stem-cell transplant, CM and exosome
therapies demonstrate preclinical and some clinical success, each one of them has its
own limitations that will need to be overcome. Stem cell transplant is a costly procedure,
and it also raises concerns for tumorigenicity24. While CM and exosomes may be more
affordable26 and safe in terms of tumor development27, 28 they both pose some problems.
The cell-free nature of CM provides a safer and more immunocompatible environment, but
makes isolating a composition-consistent CM challenging26. Similarly, there are currently
no standard effective isolation methods for exosomes39. While results are certainly hopeful,
larger and more robust double blind controlled clinical trials are needed to further assess
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the exact mechanisms, therapeutic potential and safety of stem-cell based approaches to hair
loss management.

Funding sources:
Our work is supported by the National Institute of Health grants (U01DK119085, R01NR015649 and
R01AR073614 to M. T.-C.) and research funds from the Frost Department of Dermatology and Cutaneous Surgery.

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