**5.2 Skin cell migration**

*Regenerative Medicine*

and migration [11, 16, 90–92].

**5. ADSCs' interactions with TFG-β and GDF11 for skin regeneration**

**5.1 Proliferation and differentiation of ADSCs into skin cells**

Increasing evidence has implicated ADSCs in maintaining skin homeostasis at a cellular level through cell differentiation and at the paracrine level. The exosomes they secrete respond to the hemostasis of skin microenvironment by releasing the growth factors promoting neo-angiogenesis, cell differentiation, cell proliferation,

Through their secreting growth factors, ADSCs impacted cell proliferation, migration, and senescence, which are the physiological parameters associated with wound injury and aging. During wound healing, ADSCs and DF have been reported to optimize and address their local environment, the secreted ECM proteins have been reported to modulate the activity of keratinocytes and DF through mediating secretion of growth factors such as TGF-β to activate the healing process [41–43, 69]. TGF-β plays a critical role in ECM protein production and especially collagen synthesis and degradation via the SMAD pathway [44]. Sasaki et al. were the first to identify the implication of MSCs in skin regeneration by their ability to differentiate and to repopulate damaged tissues [93]. Also, green fluorescent protein (GFP) positive bone marrow MSCs were able to differentiate into keratinocytes, endothelial cells, and pericytes presenting altogether specific cell line markers [42].

Nevertheless, other factors are secreted by ADSCs or other epithelial cells that were recently identified to pave the way to the ones reported above or even have a place of honor in favoring skin regeneration or rejuvenation. In regard to this fact, the first on the list might be the GDF11, another member of the TGF-β family recently involved in the structural and functional amelioration of skin cell and

GDF11, also known as bone morphogenetic protein-11 (BMP-11), is a disulfide-

However, the mostly important fact reported is that secreting GDF11 by ADSC originates the mechanisms related to cell differentiation and proliferation and cell migration even by upregulating genes involved in skin barrier function, in cellular proliferation, to epidermal turnover and differentiation and via modulating the TGF-β/SMAD pathway. Genes related to ECM production were also found upregulated after Smad2 and Smad3 activation, in parallel to decrease in IL-1β proinflammatory cytokine-related gene [24]. Indeed, DF produced TGF-β and GDF11 [95, 96] in addition to laminin, collagen, elastin, and fibronectin to ensure mechanical stability of the dermis and participated to epidermis cell functions including those of keratinocytes and melanocytes. ADSCs were also reported to secrete ECM

Additionally, ADSCs might be automodulated by the secreted GDF11. On the other hand, GDF11 increased MMP-9 gene expression, which is known to interact with TGF-β to help wound closure and facilitate wound healing. However, high production of this protein is expected to improve matrix remodeling after injury

linked dimer existing in a proactive form maturing after cleavage by furin-like proteases with 407 amino acids. 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 [5]. Many physiological and pathophysiological functions are attributed to this factor, including cell embryonic development, erythropoiesis, proliferation and differentiation,

cardiovascular diseases, diabetes mellitus, and age-related diseases [5, 94].

proteins participating in this activation loop.

rather than its degradation [97].

supporting skin stem cell proliferation and differentiation [23, 24].

**48**

Subcutaneous MSCs mainly identified as ADSCs were considered as the principal actor in the process of skin cell migration [93] but their presence within skin layers has not been established yet. Additionally, adipose tissue extract containing evidently ADSC's secretome was able to significantly stimulate DF migration [25].

By expressing the chemokine receptor CCR7, which is the specific receptor of SLC/CCL21 involved in cell migration, MSCs accelerated their recruitment and migrated to the injured site, thus stimulating wound repair by giving rise to differentiated skin cells *in vivo*.

TGF-β is secreted by DF, macrophages, and ADSCs and consequently amplifies angiogenesis and migration of ADSCs, keratinocytes, and DF by stimulating the SMAD2/3 pathway and increasing the expression of CXCR-4 receptor of SDF-1. This migration has been confirmed *in vitro* while ADSCs were recruited into damaged sites by SDF-1 [98], using the SDF-1/CXCR-4 axis and the intracellular Jak/AKt regulation pathway [99]. GDF11 also stimulated DF and keratinocytes to migrate into wounded sites [23]. By activating the same SMAD2/3/pathway, GDF11 and TGF-β stimulate skin endothelial cells to migrate, thus improving angiogenesis. This suggested that GDF11 activates the identical pathway in other skin cells such as DF and keratinocytes to improve cell migration and wound repair [24].

Other mechanisms leading to ADSC migration were reported after their activation by activin B, JRK, and ERK signaling appeared to be responsible for actin stress fiber formation involved in cell migration [5]. Interestingly, activin B was found to promote ADSC migration by enhancing α-SMA expression and stress fiber formation.
