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| Dr. Joel Aronowitz |
by: Joel A. Aronowitz, Daniel
Oheb, Nathan Cai, Asli Pekcan, Bridget Winterhalter, and Joseph Clayton
Abstract
Adipose derived stem cells (ADSCs) possess regenerative
properties based on their observed cellular and paracrine behavior in a large
body of preclinical lab and animal studies. These intriguing properties suggest
ADSC’s offer a unique and powerful modality for many age-related changes and
elective cosmetic treatments. ADSC’s are reported as a primary modality or
adjunct aesthetic treatment for many conditions, including senescent skin
changes, restoration of the subcutaneous adipose layer, photoaging, improvement
of hypertrophic scars, optimizing fat graft engraftment especially in small
volume applications and, most recently, hair regeneration for early androgenic
alopecia. Here, we explore the scientific rationale and range of aesthetic
applications reported for autologous ADSC’s, reported benefits, and current
limitations. Further clinical research is needed to document efficacy,
establish a dose/effect relationship and optimal method of administration. But
unquestionably ADSCs represent a significant autologous modality on the horizon
for cellular based aesthetic therapies in the face and body.
Keywords
Adipose-derived stem cells, aging,
fat grafting, wound care, photoaging, vitiligo, scarring, breast, autologous
Overview
Adipose derived stem cells (ADSCs) are small stellate shaped
pluripotential cells which reside in large numbers on the walls of small vasculature.
It is estimated that each gram of adipose tissue contains approximately 3
million of these mesenchymal cells. Although the HLA surface protein expression
of these cells is heterogenous, including CD 34, the sine qua non of definitive
identification is their tendency to adhere and form colonies in vitro (Yu 2010,
Gronthos 2001). This tendency is reported in a standard laboratory test known
as Colony Forming Units (CFU). Adipose cells expressing this ability are
further categorized by a range of tests including mRNA arrays, flow cytometry,
and transcriptomic analyses (Yu 2010, Gronthos 2001). Interest in these cells
has resulted in publications from a wide range of researchers from cell
biologists to practicing clinicians. This profusion of scientific papers often
produces a confusing terminology as authors frequently suggest updated
nomenclature to reflect an evolving understanding of the behavior of these
complex cells. In the final analysis, ADSCs may be properly classified as
mesenchymal, connective tissue pluripotential messenger cells found most
abundantly in peripheral adipose tissue. They possess the potential to
repeatedly divide 25-28 times to produce daughter stem cells. The somatic
daughter cells may differentiate to virtually any connective tissue cell type,
recruit circulating cells such as the macrophage and direct the differentiation
of these and locally resident cells. The term messenger is appended to ADSCs
because they are well known to direct the behavior of other cells through a protean
range of paracrine effects.
A large body of preclinical research elucidates the cellular
characteristics and behavior of these pluripotential cells which are found
concentrated in the stroma of adipose tissue and supports the concept of
utilizing these cells for cosmetic purposes to replace senescent volume loss
and reverse other aesthetic changes in the skin and subcutaneous tissue
observed with age such as attenuation of dermal thickness, loss of subcutaneous
adipose tissue, loss of dermal elasticity and pigment changes.
Based on the preclinical literature, clinicians applied
autologous adipose derived stem cells in the treatment of a wide variety of
aesthetic purposes. The ease of accessibility of autologous cells from adipose
tissue, their regenerative properties and a proven clinical safety profile
suggest that ADSCs offer the possibility of a unique treatment modality for
many age related and elective cosmetic treatments [1]. These applications
include restoration of volume loss and redistribution due to aging, improvement
of thin and fragile skin and reversal of unsightly pigmentary changes
associated with age and sun exposure. Most of these reports pertain to
treatment of facial senescent changes but there are many applications relating
to other areas of the body as well.
A brief summary of age associated and environmental exposure
induced changes in the skin and subcutaneous layer is necessary to understand
stem cell applications in treatment.
Age-related changes to the skin include a loss of skin
elasticity, wrinkling, decreased amount of hair follicles, and a reduction in
sweat and sebaceous glands. Overall, the epidermis regenerates at a slower rate
with age, influenced in part by slowed collagen synthesis [2]. Skin thickness
is decreased due to loss of vascularization and cell proliferation,
particularly of keratinocytes and collagen [3,4]. Changes in the structure and
adhesion levels of subcutaneous white adipose tissue reduces skin elasticity
[5]. As the number of adipose-derived stem cells decreases, the number of
adipocytes in a given area of the face decreases, reducing skin stiffness and
increasing wrinkles [5].
Environmental factors such as tobacco smoking, infrared
radiation, and ultraviolet exposure can accelerate the skin ageing process and
further contribute to wrinkles and loss of epidermal thickness [2,6].
Environmental damage to the skin, including photoaging, tends to occur more
often in males than in females [7]. Ultraviolet exposure in particular alters
skin pigmentation and texture as well [6].
Beyond aging, the skin can undergo aesthetic changes such as
vitiligo, a skin condition in which loss of melanocytes leads to skin
discoloration [8]. Though it only affects about 1% of the population, it serves
as a good example of a disorder that drives patients to seek cosmetic
treatments to preserve their appearance [9]. Traditionally, vitiligo is treated
with melanocyte transplantation [8].
With respect to the subcutaneous fat layer, the aging face
exhibits a change in the distribution of adipose tissue with age.
Three-dimensional modeling of young and old facial shapes shows an increase in
the mobility of facial tissues with age, specifically towards the lower
anterior portion of the face [10]. Overall migration of facial fat to the
inferior portion of the face contributes to a more masculine, square face and
more prominent fat pads below the eyelid [11-12]. The nasolabial fold also
becomes more defined, and loss of subcutaneous fat in the orbital area leads to
a deeper orbital rim that makes the eyes appear sunken [12]. There has been an
increase in efforts to identify more ways to address the facial volume loss a
patient might experience as they age [13].
Historically, tissue volume concerns have been addressed
with fat grafting. This technique is not only used for facial procedures but
can also be useful for breast reconstruction purposes in breast cancer patients
following mastectomy [14]. However, traditional autologous fat grafting is
limited by unpredictable rates of reabsorption, causing patients to undergo
multiple fat grafting procedures in order to maintain the desired result
[15-17]. Furthermore, there is an apparent lack of consensus regarding good
clinical practices related to autologous fat transfer procedures that further
contributes to the large variation in results [15].
Traditional treatments for aging and environment-induced
changes to the skin include topical treatments, such as retinoid creams. These
creams are meant to increase collagen synthesis and counteract the degradation
of skin cells that causes a loss of skin thickness and an increase in skin
discoloration [18-19]. Chemical peeling is another common treatment for
dermatological concerns such as photoaging to stimulate keratinocyte
regeneration [20]. However, chemical peels run the risk of a wide range of
complications, including but not limited to hyperpigmentation, skin irritation,
and scarring [21]. Preclinical and clinical research in recent years suggests
that the efficacy of these treatments rest, at least in part, from initiation
of natural tissue regeneration mechanisms through the controlled application of
a chemical, mechanical or thermal trauma. ADSCs are rapidly attracted to the
zone of injury and adipose derived stem cell’s normal regenerative activities
are likely key to the desired effects of traditional cosmetic treatments such
as dermabrasion, laser therapy, intense pulsed light, and chemical peels with
caustics or acids. The idea of activating the regenerative and anti-aging
effects of pluripotential cells without the negative effects of an inciting
trauma is fundamental to the use of cosmetic cellular therapies.
The use of mesenchymal stem cells (MSCs) as a supplement
and/or substitute for existing aesthetic treatments is promising. MSCs possess
the benefit of high availability from autologous sources, ease of isolation,
and ease of in vitro expansion.
Adipose tissue and bone marrow are two major sources of MSCs, both of which
have similar properties to each other [22]. However, adipose tissue has proven
to be a more favorable source of mesenchymal stem cells, as there are a higher
percentage of MSCs present in adipose tissue in comparison with bone marrow.
MSCs make up approximately 1% of adipose tissue, while they make up only about
.001% of bone marrow [23]. Adipose derived stem cells (ADSCs) are isolated from
Stromal Vascular Fraction (SVF), a heterogeneous population of cells isolated
from adipose tissue using a simple and safe protocol [24,1]. The umbilical cord
is also a viable source of MSCs [25]. These cells, though not autologously
sourced like adipose stem cells, do appear to enjoy the same immunologic
tolerance of all mesenchymal stem cells and clinical experience shows they can
be administered with a high safety profile. The clinical safety of these cells
depends on the integrity of the tissue bank that sources and prepares the
cells, thus FDA tissue bank accreditation is essential.
Applications of Adipose Stem Cells for Aesthetic Therapies
Tissue Volume
Traditional fat grafting techniques aiming to restore volume
to the face struggle with the limitation of a lack of volume retention
following the procedure [15-17]. This limitation may be attributed to the hypoxic
conditions the adipose graft experiences following transplantation. The process
of revascularization of an adipose tissue graft can be inefficient, causing the
graft to suffer hypoxic conditions beyond its upper limit, which is around 24
hours. The signaling pathway that connects hypoxia to apoptosis of adipose
cells is also not clearly defined [26]. The use of mesenchymal stem cells
(MSCs) in conjunction with autologous fat grafting might address this issue
[27]. Studies have identified that fat grafts enriched with adipose derived
stem cells might mitigate that drawback of fat grafting. In one such study
comparing traditional fat grafts to those supplemented with ADSCs, no patients
that received stem cell therapy had to return for another grafting procedure to
preserve volume [17].
ADSCs can be used in conjunction with lipoaspirated fat in a
method referred to as cell-assisted lipotransfer (CAL) [28]. This can be a safe
and effective option for patients interested in an increase in facial volume (Figure
29.1), as well as patients interested in breast reconstruction or buttock
augmentation (Figure 29.2-Figure 29.4) [28-30].
Dermatological Applications (*Pigmentation, thickness, elasticity,
vitiligo)
The uses of ADSCs extends beyond preservation of tissue
volume to aesthetic therapies related to the skin. ADSCs have been suggested to
kickstart the re-epithelialization process, stimulating keratinocyte production
and organizing these newly formed cells. ADSCs can also promote collagen
synthesis to further counteract the loss of dermal thickness that occurs due to
aging [4].
ADSCs reduce cell death related to UVB ray exposure,
indicating they could play a role in reducing wrinkles caused by photoaging
[31]. The antioxidative effects of ADSCs could combat the oxidative stress that
might lead to skin discoloration. Proteomic analysis of cultured ADSCs show a
wide range of antioxidant proteins in the culture, such as SOD2, PEDF, and HGF
[6]. Since antioxidants can influence melanin production, ADSCs can be a useful
skin whitening agent to counteract skin discoloration [6].
With respect to vitiligo, one study of nude mice found that
a skin graft containing both melanocytes and ADSCs was significantly more
effective than a graft of melanocytes alone, as shown by a higher increase in
overall melanocytes [8]. These findings can be reconciled with the
aforementioned skin-whitening potential of ADSCs. While ADSCs reduce the number
of Trp-1-positive mature melanocytes, they can increase the number of Trp-2
positive precursor cells that are later differentiated into melanocytes.
Preparing melanocyte grafts supplemented with ADSCs requires a particular
balance of ADSCs and melanocytes in order to combat the effects of vitiligo
[32].
Hair (Kerastem STYLE Trial)
Hair loss and the decrease in subcutaneous scalp tissue
occur simultaneously, highlighting the relationship of hair loss to adipose
tissue [33]. Conveniently, ADSCs show promise for the treatment of early
androgenetic alopecia. Results from an FDA approved Phase II clinical trial
determined that injection of fat supplemented with a low dose of ADSCs into the
scalp led to an increase in the amount of hair in subjects exhibiting the early
stages of hair loss (Figure 29.5). [34]
Improvement of Wound Healing and Scarring
ADSCs show promise for a wide array of applications in the
field of wound care. Wound care entails regular treatment of acute and chronic
wounds, often involving skin grafts. MSCs are particularly useful for this
purpose due to their immunoprivileged status as well as their ability to signal
cell proliferation [35].
One application of ADSCs in wound care is the treatment of
wound patients suffering from Diabetes Mellitus (DM). Wound healing in these
patients is challenging due to a lack of re-epithelialization of tissue as a
result of deficient cellular proliferation, similar to the lack of
proliferation that causes wrinkles in aging patients. Wounds treated with ADSCs
have shown an increased level of some of the growth factors necessary for
cellular proliferation, such as transforming growth factor-Beta1 (TGF-β1) and
transforming growth factor-Beta3 (TGF-β3) [36]. TGF-β1 is implicated in
cellular migration to a wound site, while TGF-β3 enhances collagen
organization, indicating that ADSCs might accelerate wound healing through
these mechanisms [36,6]. Moreover, ADSCs that are introduced systemically seem
to migrate to an injury site to promote growth in that area [23]. Studies have
also suggested the effectiveness of ADSCs in treatment for fibrotic scars that
might arise after a wound has healed [37].
Benefits of using Adipose Stem Cells for Aesthetic Purposes
The benefits of using adipose-derived stem cells for
aesthetic therapies are vast. An autologous and abundant sample can be
extracted from a patient’s abdominal area [36]. ADSCs possess the most promise
for isolation in a safe and minimally invasive fashion [38,1]. SVF extraction
yields a higher amount of mesenchymal stem cells compared to bone marrow and
can also be expanded in vitro in
order to increase the amount of cells available for transplantation into
patients [24,36]. Adipose derived stem cells are also immunoprivileged, lacking
the class II major histocompatibility complex (MHC-II) [23]. This makes ADSCs
ideal candidates for fat grafting procedures, minimizing the adverse immune
response of the patient [23].
Current Limitations and Future Directions for Adipose Stem Cell Treatments
Though ADSCs show a great deal of promise for aesthetic
therapies, limitations exist that merit consideration. While SVF can be
isolated easily from a patient, the resulting sample is heterogeneous,
containing fibroblasts, pericytes, smooth muscle cells, preadipocytes,
endothelial cells, and immune cells [38]. Isolation of ADSCs requires further
effort and runs the risk of an ADSC culture that is not exclusively made up of
ADSCs.
Another limitation of these therapies lies in the possible
tumorigenic effects of ADSCs. One study suggests that certain signaling
molecules such as CXCL1 that can be derived from ADSCs might increase the risk
of breast cancer recurrence [39]. Obesity also seems to play a role, altering
the properties of ADSCs [40]. One study identified that leptin secreted from
obesity-altered ADSCs might stimulate breast cancer growth through estrogen
dependent pathways [40-41]. Potential cross contamination of stem cell samples
must also be taken into account and underscores the importance of clearly
defined and closely followed protocols for cell extraction and maintenance
[42]. Further consideration should be given to these risks before implementing
ADSC related aesthetic treatments.
At the time of this publication, clinical trials are
currently recruiting to explore some of the benefits of ADSCs for aesthetic
purposes. One such study sponsored by the Medical University of Warsaw [43] aims
to explore the use of ADSC injections to treat scars. Another study, also
sponsored by the Medical University of Warsaw [44], aims to explore the
effectiveness of using ADSCs to treat chronic wounds related to diabetic foot
syndrome.
Conclusions
Adipose-derived stem cells possess a great deal of promise
for applications in aesthetic therapies ranging from anti-aging treatments to
tissue reconstruction and wound care. They have the potential to address issues
of fat graft volume retention, skin elasticity, skin pigmentation, and skin
thickness. Moreover, ADSCs can supplement wound care procedures to provide more
effective treatment. Though further research is necessary to solidify the
safety and efficacy of these treatments, current findings suggest that ADSCs
may play a pivotal role in aesthetic therapies in the near future.
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