**1. Introduction**

Skin covers the human body and acts as a protective barrier against external aggressions; it consists of three component layers: epidermis, dermis, and hypodermis. Skin also has a pivotal role in thermoregulation, water retention, and cell regeneration. However, the skin remains the first exhibition of time passing characterized externally by skin winkles' manifestations, loss of integrity elasticity and functionality. These processes vary between individuals but altogether reflect

cellular and molecular changes leading to progressive reduction in cell proliferation and regeneration as a result of increasing cell senescence and apoptosis [1].

A recent work has testified that adult multipotent stem cells are present in the dermal sheets and in the interfollicular dermis; they can also be derived from the pericytes [2]. They are expected to play a crucial role in regulating skin function and turnover. Furthermore, these cells were considered as mesenchymal stem cell (MSC)-like expressing the specific mesenchymal markers and differentiating into adipocyte, chondrocyte, osteoblast and myocyte [3]. These cells are identified within the subcutaneous adipose tissue as adipose-derived stem cells (ADSCs) and have been reported to differentiate into skin cells, thus ensuring skin regeneration and maintaining homeostasis [4–6]. Several studies have shown the ability of ADSCs to act through cell-cell contact, but mostly by secreting a panel of cytokines and chemokines, being involved in different biological pathways including cell proliferation, differentiation, homing and migration, senescence, and apoptosis [7–11]. These mechanisms are implicated in the whole process of skin regeneration during wound healing.

ADSC-based therapy is very promising in treating damaged tissues and in completing full-thickness skin replacement. Some clinical applications benefit from its simple and abundant collection from adipose tissue. The capacity of these cells to proliferate and self-renew *in vitro* as well as *in vitro* added to their innate differentiation has targeted more scientific advancements in the field of regenerative medicine. Their immunomodulatory effects also make them more suitable for use compared to their counterpart from bone marrow and umbilical cord blood [12]. These cells have been used for many investigations and are largely used for graft improvement in cosmetic remodeling to prevent fat necrosis [13–15]. ADSCs have presented a great ability to migrate and were recruited rapidly into wounded sites where the process of cell differentiation toward various skin cell components occurred. ADSCs have helped in cicatrization and regulating inflammation and the phases of wound healing [6]. These cells secrete growth factors in their extracellular vesicles [16–18] and produce different amounts of the extracellular matrix (ECM) proteins, thus promoting and accelerating skin regeneration in 3D raft cultures from adult expanded human skin [19, 20]. This suggested that these cells represent a rich source of factors necessary for accelerating wound healing and tissue regeneration.

Among the secreted growth factors, transforming growth factor-β (TGF-β) and growth differentiation factor 11 (GDF11) are highlighted and both are involved in biology of skin and different organs [5, 21, 22]. Both factors belong to the same superfamily of TGF-β and target similar skin cells including dermal fibroblast (DF), keratinocytes, melanocytes, and dermal microvascular endothelial cells [23–25]. Moreover, these factors activate the intracellular SMAD signaling pathways, thus targeting skin cell properties to repair wounded tissues. Consequently, TGF-β reduces wrinkles and photoaging signs [24, 26, 27]. On the other hand, GDF11 has received more attention with its ability to produce age-reversing effects [25, 28] and increase skin cell proliferation and functionality [23–25].

In the current research, many questions have been raised about the involvement of GDF11 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 in this cascade, an interaction between GDF11 and TGF-β for sustainable skin biology and function has been suggested. Additionally, they share similar intracellular mechanisms involved in healing and aging. Cross-talking with the surrounding cells, mainly resident ADSCs, keratinocytes, DF, melanocytes, and macrophages, these factors might be activated, autoactivated, and/or mediate other cytokines and chemokines to attain and orchestrate even similar

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wound healing.

**2. Skin: anatomy and physiology**

present within the epidermis.

*Adipose-Derived Stem Cells (ADSCs) and Growth Differentiation Factor 11 (GDF11)…*

mechanism pathways but taking advantage for skin repair and cell regeneration or cell rejuvenation through resident's stem cell proliferation and differentiation. When secreting TGF-β and GDF11, ADSCs underwent autoinduction by binding these factors to their transmembrane specific receptors ActIIBR and TGF-βR respectively and initiating the intracellular signal transduction cascade. However, circulating GDF11 has been reported to decrease with age [21, 29] and, in the same way, younger ADSCs and MSCs were found to be more proliferative, secrete more ECM proteins, and be more rejuvenating as compared to the aged ones [18]. On the other hand, positive effects on skin vasculature, skin integrity, density and strength, and wrinkles reduction have been reported when using recombinant GDF11 (rGDF11) [24] likely by cross-talk between DF, keratinocytes, ADSCs, and endothelial cells. Its beneficial involvement in skin microvasculature impaired during aging is highly expected through proliferation and differentiation of progenitor endothelial cells [30]. Other reports suggested that TGF-β was more involved in skin repair and cell regeneration during normal biological process or after injury and is considered as a key tool in the regulation of wound healing by promoting angiogenesis, cell proliferation, and migration [31]. Through its immunoregulating capacity, TFG-β and GDF11 were also specifically implicated in skin inflammatory process during wound healing and skin aging or inflamm-aging by downregulating

However, the relationships between TGF-β and GDF11 are not fully understood. With regard to their secretion levels and the skin regeneration and youth during aging, an expected ratio of TFG-β/GDF11 might be considered and regulated in a spatio-temporal manner and balance the whole cellular and molecular mechanisms associated to regeneration or rejuvenation. These regulating aspects must draw more attention as an important potential target attaining antiaging processes during

Skin thickness varies between people and with age and ranges on average from 0.05 to 2 mm. Skin is comprised of three layers: non-vascularized and stratified epidermis, underlying the dermis composed of a connective tissue and the subcutaneous adipose tissue forming the hypodermis including the adnexal structure [34]. The epidermis is preceded by an organized structure the *stratum corneum* formed by as interdigitated dead cells called corneocytes disposed as bricks between multiple lipid bilayers holding the structure defined as "brick and mortar" [35] and represent the first barrier to external factor penetration. The viable layers of the epidermis are *stratum lucidum*, *stratum granulosum, stratum spinosum,* and *stratum germinativum*. Keratinocytes composing these layers undergo progressive differentiation from the basal *stratum germinativum* to the outermost layer. These self-renewal and differentiation processes are important for epidermal regeneration and lead to generation of solid lipid-rich cornified layers [36]. Melanocytes are other cells present in the epidermis; they synthetize the melanin pigment being transferred to mature keratinocytes, providing principal skin protection against UV damages. Merkel cells, dendritic cells, adipocytes, and Langerhans cells are also

Fibroblasts are the principal cells constituting the dermis; they are mesenchymal and represent skin scaffolds where they support other epithelial cells and the epidermis through their elongation and shaped form, but especially through secretion of fibrous and elastic components constituting the ECM responsible for cutaneous strength and elasticity [34]. ECM is composed of fibrous proteins and a ground

*DOI: http://dx.doi.org/10.5772/intechopen.91233*

proinflammatory cytokine genes expression [32, 33].

#### *Adipose-Derived Stem Cells (ADSCs) and Growth Differentiation Factor 11 (GDF11)… DOI: http://dx.doi.org/10.5772/intechopen.91233*

mechanism pathways but taking advantage for skin repair and cell regeneration or cell rejuvenation through resident's stem cell proliferation and differentiation.

When secreting TGF-β and GDF11, ADSCs underwent autoinduction by binding these factors to their transmembrane specific receptors ActIIBR and TGF-βR respectively and initiating the intracellular signal transduction cascade. However, circulating GDF11 has been reported to decrease with age [21, 29] and, in the same way, younger ADSCs and MSCs were found to be more proliferative, secrete more ECM proteins, and be more rejuvenating as compared to the aged ones [18]. On the other hand, positive effects on skin vasculature, skin integrity, density and strength, and wrinkles reduction have been reported when using recombinant GDF11 (rGDF11) [24] likely by cross-talk between DF, keratinocytes, ADSCs, and endothelial cells. Its beneficial involvement in skin microvasculature impaired during aging is highly expected through proliferation and differentiation of progenitor endothelial cells [30]. Other reports suggested that TGF-β was more involved in skin repair and cell regeneration during normal biological process or after injury and is considered as a key tool in the regulation of wound healing by promoting angiogenesis, cell proliferation, and migration [31]. Through its immunoregulating capacity, TFG-β and GDF11 were also specifically implicated in skin inflammatory process during wound healing and skin aging or inflamm-aging by downregulating proinflammatory cytokine genes expression [32, 33].

However, the relationships between TGF-β and GDF11 are not fully understood. With regard to their secretion levels and the skin regeneration and youth during aging, an expected ratio of TFG-β/GDF11 might be considered and regulated in a spatio-temporal manner and balance the whole cellular and molecular mechanisms associated to regeneration or rejuvenation. These regulating aspects must draw more attention as an important potential target attaining antiaging processes during wound healing.
