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Journal of Embryology & Stem Cell Research Research Article 24 min read

Growth Differentiation Factor 11 (GDF11)/Transforming Growth Factor-β (TGF- β)/Mesenchymal Stem Cells (MSCs) Balance: A Complicated Partnership in Skin Rejuvenation

Mazini L*, Rochette L and Malka G
* Corresponding author
ISSN: 2640-2637  10.23880/jes-16000122  Received: July 29, 2019  Published: August 19, 2019
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Keywords
Skin Mesenchymal Stem Cells Dermal Fibroblasts Wound Healing Aging TGF-β GDF11
Abstract

Different theories on how cells aged and many strategies to overcome this have been thought and retained much more attention in designing research in tissue regeneration and skin anti-aging. Mesenchymal stem cells (MSCs) have showed great interest since identified as residual stem cells in almost adult organs. These cells presented great ability in migration and were recruited rapidly into wounded sites where process of cell differentiation towards various skin cell components occurred. MSCs senescence may be involved in the loss of tissue homeostasis, which could lead to organs failure and development of age-related diseases. Several studies have demonstrated that intravenously injected MSCs can migrate specifically to the sites of tissue damage, such as those caused by ischemic conditions or inflammation. A continuous state of inflammation in the wound creates a cascade that perpetuates a nonhealing state. During the inflammatory phase, MSCs coordinate the effects of inflammatory cells and inhibit the deleterious effects of inflammatory cytokines. Different proteins are secreted by these cells such as vascular endothelial growth factor (VEGF), Transforming Growth Factor-β (TGF-β), and Growth Differentiation Factor 11 (GDF11) are the key tools for ensuring tissue regeneration. The mechanisms inducing tissue degeneration and cell aging remained multifactorial and still unclear. The skin undergoes constant changes, with a high capacity of repair and renovation. In wound healing, evidence established the involvement of MSCs and dermal fibroblasts (DF) through sirtuins and SMAD pathways. Moreover, the mainly and recently studied secretome of MSCs is the extracellular vesicles involved in migration and proliferation of DF and keratinocytes where GDF11 and TGF-β were expected to play the principal role. Theoretically identical MSCs populations from individuals may display different secretome properties, depending on factors including age and health status. Another source of adult stem cells, called adipose-derived stem cells (ADSCs), is relatively newer and less invasive with asimilar cell differentiation potential. Further in-depth studies are needed to clarify the relationships between these factors in promoting wound healing and antiaging process. These new approaches might be adapted for various cell types and the specific secretome promising for application in regenerative medicine.

Introduction

Rejuvenation is the undeniably the major concern of all peoples through time. Based on alchemy and mysticism, the attained unique objective was to identify the youth elixir. Nobody expected that this elixir really exists within our own cells.

Different theories on how cells aged and many strategies to overcome this have been thought and retained much more attention in designing research in tissue regeneration and skin anti-aging. Even age- dependent aging or photo-aging, these intrinsic and extrinsic factors were associated with wrinkles, elasticity loss, discoloration, irregular and dysfunction of pigmentation, hyperkeratosis and many other symptoms [1, 2]. These manifestations rely on the impairment of a biological mechanism known as cell senescence, a multifactorial event leading to skin integrity loss.

To promote skin regeneration and ensure rejuvenation, most of strategies were based on the promising ability of multipotent stem cells to enhance cell proliferation, extracellular matrix (ECM) production and growth factors secretion. In this case, mesenchymal stem cells (MSCs) have showed great interest since identified as residual stem cells in almost adult organs. MSCs remain a promising tool for regenerative medicine as the efficacy of MSC-based cell therapy has been demonstrated for a broad spectrum of indications. Resident MSCs in skin are indeed playing an important role in wound healing and rejuvenation processes [3]. These cells have been demonstrated to differentiate into fibroblasts inducing thus ECM production [4]. They are located at the base of the hair follicle (dermal papilla cells), in the dermal sheets (dermal sheet cells), in interfollicular dermis and could derived likely from the perivascular pericytes [5, 6]. MSCs secrete a variety of autocrine/paracrine factors, called secretome, that support regenerative processes in the damaged tissue. MSCs display a rich secretory profile and express a variety of chemokines and cytokines that aid in repair of degraded tissue, restoration of normal tissue metabolism and counteracting inflammation. Recently, the secretome of MSCs have drew more attention as a mechanism governing skin repair and regeneration through stimulatory factors secretion [7, 8]. Within this secretome, proteins such as Vascular Endothelial Growth Factor (VEGF), Transforming growth Factor-β (TGF-β), Growth Differentiation Factor 11 (GDF11), Stromal Derived Factor-1 (SDF-1) and basic-Fibroblast Growth Factor (b-FGF) have come to the light as key tools ensuring tissue regeneration and rejuvenation [6, 9].

In wound healing, the mainly and recently studied secretome is the extracellular vesicles involved in migration and proliferation of dermal fibroblasts (DF) and keratinocytes including collagen and elastin deposition [10, 11, 12, 13, 14, 15]. At the same way, authors reported similar positive effects of MSCs-conditioned media on skin aging manifestations [9, 16, 17, 18, 19]. All these secreted growth factors are able to act directly on skin cell properties and specifically on DF inducing thus angiogenesis and enhancing ECM production, thus allowing structural support and accelerating cell growth whereby antiaging process is attained. This interplay between MSCs secretion and the other epidermal progenitors seems to orchestrate the hierarchical process of regeneration and repair by an important MSCs-resident cells crosstalk in aging or after injury. Interestingly, wound healing was specifically associated to microRNA and protein transfer to skin cells through the TGF-β/SMAD2 pathway; TGF-β being identified as a “mediator” [14, 20, 21, 22].

This SMAD pathway is also strongly involved in the aging process through the GDF-11 highlighted during cell rejuvenation and aging damage [9, 23]. GDF11 is a member of the TGF-β superfamily playing a pivotal role in cell development and aging. Circulating GDF-11 level has been associated with aging in many human organs [9,24-

28] as well as in animal models [29, 30, 31]. This factor is expressed in embryonic tissues while mRNA and protein levels were differently appreciated with higher protein levels in soft tissue, cerebral cortex, adrenal gland, testis and hippocampus [32, 33]. MSCs derived from umbilical cord blood secreted significantly higher amounts of GDF11 compared to those from bone marrow and adipose tissue [9] and appeared highly concentrated in platelets [34]. In current research, this factor has raised many questions about its involvement in the inflammatory, proliferative and remodeling phases of wound healing. Adding to the fact that TGF-β was secreted by utmost epithelial cells and participated extensively to this cascade, the suggestion of an interaction of GDF11 and TGF-β for a sustainable skin biology and function have become more appropriate. In this review, we will try to reveal the potential of GDF11/TGF-β mechanisms in normal and wounded skin and to understand the paradigms which trigger during cell life a potential balance between cell regeneration and aging-associated mechanisms.

GDF11/TGF- β Interferences in Skin Biology

Aging is undeniably associated to a decline in most of organ’s functionality. The severity of this decline remained mainly dependent of health history, quality of life and genetic factors [35] (Rochette L et Mazini M 2019 submitted). The mechanisms inducing tissue degeneration and cell aging remained multifactorial and still unclear. Impaired skin regeneration failed to ensure maintenance of the barrier and prevent its protection from pathological conditions. During normal development, skin regenerative capability is performed by the resident MSCs providing for cellular turn over during skin homeostasis and repair after injury [36]. Basal layer is the skin location where these active multipotent stem cells are responsible for recruiting and sending mature differentiated cells (keratinocytes) to the outer of epidermis. Through a hierarchic gradient, these stem cells induced epidermis layer regeneration by ensuring self- renewal and a continuously production of transient amplifying cells [37]. Fibroblasts were also recognized to play a crucial role in skin regeneration through GDF11 secretion in both neonatal and adult cells [38]. Kim Y, et al. have demonstrated that GDF11 activated fibroblasts to increase ECM proteins production and especially collagen 1 and 3 and fibronectin [9].

Wound Healing

MSCs presented great ability in migration and were recruited rapidly into wounded sites where process of cell differentiation towards various skin cell components occurred [39]. ADSC identified within the basal layer might influence the physiological characteristics of the injured skin. During the proliferation phase, cytokines and chemokines secreted by these cells were involved in several fibroblasts’ characteristics such as cell proliferation, migration and specifically collagen synthesis and other ECM proteins connected with tissue repair and regeneration [40, 41, 42]. Indeed, conditioned media from ADSCs, umbilical cord- and amniotic fluid- MSCs significantly enhanced proliferation of DF [43]. Involvement of MSCs and DF are essential for the cascade of the factors related to skin regeneration and reflected the importance of endogenous compounds such as sirtuins and SMAD pathways [44, 45]. The sirtuins are a family of proteins that comprise class III of the histone deacetylases. These NAD+-dependent proteins have been found to be intricately involved in a variety of important and skin-relevant cellular functions and processes, including aging, UV damage response, and wound repair. Various endogenous factors have proven evidence of their crucial role in angiogenesis especially the VEGF. These ADSCs were reported to secrete ECM supporting thus the skin structure under normal and healing conditions [46, 47]. The proteins of this ECM were reported to modulate the activity of keratinocytes and DF through mediating growth factors secretion such as TGF-β to activate healing process [48, 49]. Recently, the collagen triple helix repeat containing 1 protein contributed to healing process via increasing M2 macrophages recruitment and TGF-β expression level [50]. On behalf the secreted proteins involved in this wound healing, the TGF-β/SMAD 2 pathways were increased and DF induced. TGF-β receptor has been identified in MSCs [40] and its activation resulted in enhancing MSCs homing ability CXC chemokine receptor 4 (CXCR4) dependent. CXCR4 regulates the retention of stem/progenitor cells in the bone marrow and other tissues [51, 52].

At the other side, GDF11 has been recently associated to skin aging. However, there are discrepancies between its serum levels reported and first studies did not relate on the decrease of its circulating level during aging [24]. Improving GDF11-antigen specificity versus myostatin, the other TGF-β family sharing with it more than 90% of its amino acid sequences, has demonstrated this decrease in animal models [53] and in human [26, 54].

Many reports have demonstrated that GDF11 levels were related to disturbance in sustainable biological process in many organs as in cardiovascular diseases [28, 55], in skin wounds [56] and in neurologic deficits [57]. Nevertheless, when activation of SMAD2/3 pathways through GDF11 and its specific receptor membrane Activin type IIB (ActIIBR) occurred on MSCs, similar mechanism might be achieved by TGF-β, suggesting that interference with TGF-β and GDF11 mechanisms might be the key regulator of healing and aging. If there is a relationship between both factors acting on the same cell, one might be able to speculate that healing process could be modulated by balancing the TGF-β pathway.

Skin Pigmentation

During a single day in the sun, each exposed keratinocyte receives up to 105 ultraviolet (UV) photoproducts in its DNA. Therefore, an elaborate system is needed to repair UV-induced damage. Skin pigmentation can be altered owing to the direct and indirect effects of solar radiation on melanocytes. Indeed, solar radiation directly affects melanocyte homeostasis through the induction of well- defined structural alterations in DNA. Skin pigmentation can also be activated as a photo protective and adaptive mechanism against the effects of UV radiation on skin. In this context, the crosstalk between keratinocytes, fibroblasts, immune cells, and melanocytes is mediated by paracrine signaling cascade. Among the endogenous protective factors, the central process is the endogenous MSCs which coordinate the repair response by recruiting other host cells and secreting growth factors and matrix proteins.

Evidences of implications of MSCs in dermal and epidermal proliferation have suggested that these cells might impact melanocyte functions in physiologic and wounded tissues. Derived from human adipose, MSCs increased their TGF-β secretion inducing melanocytes to down-regulate the expression of melanogenic enzymes and prevent site-specific pigmentation in reconstructs skin grafting. These interactions might be of interest in clinical application by modulating melanin synthesis [58]. These cells increased TGF-β secretion maintaining thus melanocytes in an immature state. Dermal fibroblasts also acted on melanocytes by secreting cytokines and growth factors as TGB-β modulating melanin-producing enzymes and thus skin pigmentation [59], suggesting that dermal composition in cells might determine the production of mature melanocytes and hence melanin transfer to keratinocytes. Klar et al have demonstrated the crucial role of TGF-β in the whitening of skin [58]. However, a recent study has shown that recombinant GDF11 (rGDF11) significantly reduced melanin production in melanocytes and 3D skin equivalents [60]. Moreover, by increasing collagenase Matrix metalloproteinase-9 (MMP-9) secretion, rGDF11 participated in matrix remodeling maybe through interaction of MMP-9 with TGF-β1 to facilitate skin wound closure [61, 62].

Skin Aging

Skin aging is an apparent process associating morphologic disgraces and structural deficits. ECM mainly secreted by DF are composed of glycosaminoglycans, collagen type I and III and elastin and is continuously modified by physiological and extrinsic factors. UV- induced oxidative stress and energy metabolism alterations could also be a possible skin aging process and are responsible for the degradation of this ECM leading to an increase in enzymatic activity associated with collagen degeneration and loss of mechanical functions such as elasticity [63].

Other intrinsic factors are actually known to impair physiological functions of the skin and associated to cell senescence including DNA damage [64, 65], telomeres shortening [66] and reactive oxygen species (ROS) production [67]. All these processes show major roles in inducing tissue-aging and carcinogenesis [68, 69]. However, recent studies have demonstrated that this senescence can be induced by TGF-β /SMAD as a normal developmental process. Otherwise, an interesting concept of paracrine senescent cells have been proposed by Lunyak, et al. [70] where resident senescent MSCs can trigger and reinforce senescence within their microenvironment. This paracrine effect can be transmitted by ligands of TGF-β by mediating changes in the transcriptional program through SMAD family members [71].

Nevertheless, ADSC and DF appeared more attractive in term of protein secretion [72]. ADSC-conditioned media were anti-apoptotic and ensure skin tissue regeneration [19, 73, 74] and protected DF by increasing their superoxide dismutase and glutathione peroxidase activities [63]. This MSCs-conditioned medium has been reported to stimulate and enhance DF proliferation and ECM production. An anti-wrinkle effect and dermal density increase were shown after in vivo treatment [9]. Moreover, the young cells supported higher proliferation rate of keratinocyte stem cells than those from aged donors [75]. Interestingly, GDF11 expression and activity were reduced in adult DF compared to the neonatal ones [38] as its expected for MSCs [76].

ADSC were present within hypodermis cellular components suggesting their benefit in preventing skin aging induced by ROS production. In addition, these cells have been largely reported to induce re-epithelialization of injured skin and are used as promising therapy for remodeling and cosmetic surgery [16, 77]. Indeed, ADSC have proven their superiority in improving and increasing dermal thickness and reducing wrinkles more likely by inducing paracrine dermal fibroblasts and angiogenesis [77, 78, 79]. Administrated intradermally to an aged skin, skin texture and wrinkles as well as dermal thickness were found improved 8 weeks after treatment [80].

Discussion

Finally, MSCs senescence may be involved in the loss of tissue homeostasis, which could lead to organs failure and development of age-related diseases. Several studies have demonstrated that intravenously injected MSCs can migrate specifically to the sites of tissue damage, such as those caused by ischemic conditions or inflammation. In this context, MSCs display a rich secretory profile and express a variety of chemokines and cytokines that aid in repair of degraded tissue, restoration of normal tissue metabolism. MSCs are considered as the best candidate in tissue repair and regenerative medicine. They seemed likely to act through a secretome release pathway rather than cell replacement [32, 81]. Another surprising capacity of these cells is that MSCs from a young donor are more proliferative than cells of an elderly individual [77]; this process is a new way of cell therapy without cells [72, 82], via the potential directed secretome of these cells towards a tissue regeneration or rejuvenation. GDF11 and TGF-β present within this secretome are involved in many biological mechanisms including cell proliferation, tissue repair and rejuvenation. These both signaling have been reported to promote cancer metastasis [83, 84]. In skin biology, GDF11 significantly increased genes expression related to ECM production, to maintenance of skin barrier function, to skin cell proliferation and to epidermal turnover and differentiation [60] by triggering SMAD signaling in a TGF-β like fashion, suggesting that intracellular messengers related to TFG-β regulated the changes in GDF11 secretion and impact on skin architecture and function.

We cannot exclude that MSCs secreted other cytokines than GDF11 and TGF-β, such as Platelets Derived Growth Factor, Interleukin-1, Bone Morphogenic Protein (BMP)6, BMP9, might exert an autocrine and paracrine effects on DF and keratinocytes promoting cell differentiation, proliferation and migration. Nevertheless, the antiaging paracrine effect seemed to be induced, perhaps not exclusively but at least to a significant degree, by a combinatorial effect of both GDF11 and TGF-β. It’s probably that both signals vary with age and that the strength of each of them is reciprocal to the sites of secreted signals and to the length of the exposure to the signal. Based on these considerations, further investigations on TGF-β and GDF11 molecular mechanisms implication on skin rejuvenation are needed to increase the knowledge and draw conclusions on the regulation of aging process.

Conclusion

Due to complex composition of MSCs secretomes and its relationships between the other skin cell components, it was necessary to focus on the specific promising growth factors that would reflect the regenerative potency in the process of skin aging. These new approaches might be adapted for various cell types and their specific secretomes promising for application in regenerative medicine. The ability of MSCs to promote the transition from the inflammatory to the proliferative phase is particularly critical for treating chronic wounds. Many efforts are under way to develop novel bioengineered wound-healing products and considering the role of MSCs in the wound-healing process.

Authors Contributions

All authors participated in the research and writing of this manuscript

Funding

This work was supported by the University Mohammed VI polytechnic, Ben Guérir, Morocco

Conflicts of Interest

The authors declare no conflict of interest

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@article{mazini2019,
  title   = {Growth Differentiation Factor 11 (GDF11)/Transforming Growth
Factor-β (TGF- β)/Mesenchymal Stem Cells (MSCs) Balance: A
Complicated Partnership in Skin Rejuvenation},
  author  = {Mazini L, Rochette L and Malka G},
  journal = {Journal of Embryology & Stem Cell Research},
  year    = {2019},
  volume  = {3},
  number  = {2},
  doi     = {10.23880/jes-16000122}
}
Mazini L, Rochette L and Malka G (2019). Growth Differentiation Factor 11 (GDF11)/Transforming Growth
Factor-β (TGF- β)/Mesenchymal Stem Cells (MSCs) Balance: A
Complicated Partnership in Skin Rejuvenation. Journal of Embryology & Stem Cell Research, 3(2). https://doi.org/10.23880/jes-16000122
TY  - JOUR
TI  - Growth Differentiation Factor 11 (GDF11)/Transforming Growth
Factor-β (TGF- β)/Mesenchymal Stem Cells (MSCs) Balance: A
Complicated Partnership in Skin Rejuvenation
AU  - Mazini L, Rochette L and Malka G
JO  - Journal of Embryology & Stem Cell Research
PY  - 2019
VL  - 3
IS  - 2
DO  - 10.23880/jes-16000122
ER  -