**6. TGF-β and GDF11 impacts on immunoregulatory effects of ADSC in skin**

Evidence of involvement of ADSCs in immunomodulation of tissues and their presence within the epidermal layer have suggested that these cells might play a crucial role in skin immunological functions in physiologic and injured skin. Accumulation of senescent cells is related to the production of proinflammatory factors such as IL-6, IL-8, and TNF-α; we can postulate that the associated chronic inflammation is a promoting age-associated disease due to tissue aging. This skin inflamm-aging was also supported by highly secreted proinflammatory cytokine IL-1 β [32, 33]. Microvascular endothelial cells also interact with ADSCs to increase secretion of IL-6, IL-8, and MCP-1 to modulate skin inflammation [72].

TFG-β, secreted by ADSCs and other epithelial cells, is involved in the inflammatory, proliferative, and remodeling phases of wound healing. This factor activates M2 macrophages and secretion of ECM proteins involved in skin structure repair, in angiogenesis, in DF proliferation and cell migration, and re-epithelialization.

The integrin αβ6 secreted by epithelial cells was reported to activate TGF-β modulation and thus the innate immune surveillance in skin [89]. Recently, the collagen triple helix repeat containing one protein was reported to contribute to healing process via increasing M2 macrophages recruitment and TGF-β expression level [103].

In the same way, IL-6, the major proinflammatory component of ADSC's secretome, was reported to initiate the inflammatory phase in injured tissues. Autoactivated ADSCs amplify their secretion and stimulate the secretion of TNF-α, TLR2, TLR4, IL-10, b-FGF, VEGF, TGF-β, and GDF11. These secretions would take place to short and shift the ADSCs profile to an anti-inflammatory profile and enhance angiogenesis, cell migration, and proliferation (**Figure 2**). Like TGF-β,

#### **Figure 2.**

*Immunomodulatory effects of ADSCs. Through their secretome, these cells change the macrophages' polarization and acquire an anti-inflammatory profile to enhance skin cell proliferation and migration and accelerate angiogenesis.*

**51**

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

GDF11 was found to be associated to the skin inflammatory status in both physiological process and injury and participate in the regulation of the immune

To determine the effect of GDF11 on skin inflammation, a recent work of Wang et al. has shown that skin treatment with rGDF11 decreased the secretion of inflammatory cytokines by immune cells *in vitro* and *in vivo* in mice models of psoriasisassociated inflammation, an extended infiltration of immune cells sustaining skin inflammation. Suppression of the severity of this inflammation by GDF11 was achieved by reducing macrophages infiltration to the skin and inhibiting the NF-kB signaling pathway [51]. Moreover, macrophages activation has been reported in skin autoimmune inflammatory diseases [104]. Other evidences argued on the protective effect of GDF11 from inflammatory reaction by inhibiting inflammatory responses in RAW264.7 macrophages [105], probably by inhibiting TNF-α release [106]. Additionally, TNF-α was activated by NF-kB signaling pathway during inflammation reaction, being suppressed by GDF11 in atherosclerosis. By reducing the NF-kB pathway, GDF11 also protected against apoptosis [105]. This suggested that the anti-inflammatory effect of GDF11 could open the way to potential new

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

strategies for treating skin inflammations.

appeared to be strongly associated (**Figure 1**).

**7.1 Cellular implication**

culture expansion [107].

**7. Antiaging mechanisms of ADSC within TFG-β and GDF11**

The mechanisms inducing tissue degeneration and cell aging remain multifactorial and still unclear. Senescent ADSCs were likely found to be impacted in their ability to sustain tissue hemostasis and hence resulted in loss of tissue and organ integrity. Even these cells display a rich secretory profile; their ability to secrete ECM proteins, cytokines, and chemokines was largely impaired *in vitro* during

A recent clinical study has demonstrated that secretome of adipose tissue lipoaspirate extracellular fraction stimulates epidermal and dermal cell proliferation in a dose-dependent manner. This secretome has also the ability to delay apoptosis, enhance fibroblasts proliferation and migration, and reverse specifically the aging process and the associated skin symptoms [25, 28]. Exposure of fibroblasts to UVA was followed by preventing the upregulation of MMP1, MMP2, and α-SMA expression as well as lower elastin and collagen production associated to the senescence-like phenotype [25]. Indeed, ADSCs have proven their superiority in improving and increasing dermal thickness and reducing wrinkles more likely by inducing paracrine DF and angiogenesis [17, 18, 108]. Administrated intradermally to an aged skin, skin texture and wrinkles as well as dermal thickness were found improved 8 weeks after treatment [74]. The extracellular vesicles released in ADSCs' secretome or conditioned media enable the targeted cells to increase the production and deposition of ECM proteins including collagen and elastin [11, 16, 90, 109, 110]. Among these autocrine/paracrine factors, TGF-β and GDF11

Indeed, ADSCs-conditioned media *in vitro* and *in vivo* have proven their efficiency in stimulating rejuvenation of human skin by improving skin elasticity and reducing wrinkles in a GDF11-dependent manner [111–113]. Their extract acted in a similar manner by activating DF and keratinocytes to proliferate and migrate into damaged sites [114]. An anti-wrinkle effect and dermal density increase were shown after *in vivo* treatment [23]. Moreover, the young cells secreting more GDF11 supported higher proliferation rate of keratinocyte stem cells than those from aged

response.

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

GDF11 was found to be associated to the skin inflammatory status in both physiological process and injury and participate in the regulation of the immune response.

To determine the effect of GDF11 on skin inflammation, a recent work of Wang et al. has shown that skin treatment with rGDF11 decreased the secretion of inflammatory cytokines by immune cells *in vitro* and *in vivo* in mice models of psoriasisassociated inflammation, an extended infiltration of immune cells sustaining skin inflammation. Suppression of the severity of this inflammation by GDF11 was achieved by reducing macrophages infiltration to the skin and inhibiting the NF-kB signaling pathway [51]. Moreover, macrophages activation has been reported in skin autoimmune inflammatory diseases [104]. Other evidences argued on the protective effect of GDF11 from inflammatory reaction by inhibiting inflammatory responses in RAW264.7 macrophages [105], probably by inhibiting TNF-α release [106]. Additionally, TNF-α was activated by NF-kB signaling pathway during inflammation reaction, being suppressed by GDF11 in atherosclerosis. By reducing the NF-kB pathway, GDF11 also protected against apoptosis [105]. This suggested that the anti-inflammatory effect of GDF11 could open the way to potential new strategies for treating skin inflammations.
