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Adipose derived stem cells (ADSCs) Immunomodulation Impact on Skin Tissue Repair

Mazini L1*, Rochette L2, Amal S3, Admou B4 and Malka G1 1Stem Cells and Cellular and Tissue Regeneration Laboratory, Medical Applications Interface Review Article Center (CIAM), Mohammed VI Polytechnic University, Ben-Guerir, Morocco Volume 4 Issue 1 2Host Team (EA 7460), Cerebro-Cardiovascular Physiopathology and Epidemiology (PEC2), Received Date: February 06, 2020 University of Burgundy-Franche Comte, Dijon, France Published Date: February 14, 2020 3Department of Dermatology, University Hospital Center, Marrakech, Morocco DOI: 10.23880/jes-16000136 4Immunology laboratory, Clinical Research Center, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Morocco

*Corresponding author: Loubna Mazini, Stem Cells and Cellular and Tissue Regeneration Laboratory, Medical Applications Interface Center (CIAM), Mohammed VI Polytechnic University, 43 150 Ben-Guerir, Morocco, Tel: +212666392899; Email: [email protected]

Abstract

in vitro and in vivo Adipose derived stem cells (ADSCs) have largely proven their efficiency in wound healing and skin regeneration . They are niched within the hypodermis where they differentiate into skin cell types and migrate to wounded sites to restore cell deficiencies and functions. ADSCs mainly act by an autocrine pathway through their secretome containing growth factors, cytokines and microRNA (miR) involved in their migration and proliferation and that of dermal fibroblasts (DF) and skin tissue repair. Their secretome is implicated in immune responses and is considered as the key tool in regulating skin keratinocytes. There are evidences arguing that the immunomodulation capacity of ADSCs reflect their efficacy to ensure

inflammation and diseases-associated inflammation. By their action on skin immune cells, ADSCs are expected to play the especially M1 and M2 macrophages and inhibition of Th cells; iii: the skin cell differentiation, proliferation, pigmentation and principal role by modulating: i: the expression of the inflammatory factors; ii: the activation and maturation of immune cells

migration and iv: the secretion of the extracellular matrix (ECM) proteins. Additionally, ADSCs cross-react with the different skin cells, ECM and the surrounding growth factors to initiate and accelerate the implementation of all phases of wound healing. In this review, we highlight the role of ADSCs in deriving tissue repair with regard to their immune-modulation ability, this impressive capacity should be considered when using ADSCs in regenerative medicine. Keywords:

Adipose Derived Stem Cells; Skin; Immunomodulation; Regeneration; Repair; Inflammation; Wound Healing Abbreviations: ADSCs: Adipose Derived Stem Cells; Interleukin-1, -6, -8, -10; TNF-α: Tumor Necrosis Factor-α; Fibroblasts;GDF11: Growth MSCs: Differentiation Mesenchymal Factor; Stem Cells;TGF-β: IL-1, Transforming -6, -8, -10: VEGF: Vascular Endothelial Growth Factor; PDGF: Platelets Growth Factor; ECM: Extracellular Matrix; DF: Dermal Derived Growth Factor; MCP-1: Monocyte Chemoattractant Protein-1; b-FGF: Basic-Fibroblast Growth Factor; TLR2, Adipose derived stem cells (ADSCs) Immunomodulation Impact on Skin Tissue Repair J Embryol Stem Cell Res 2 Journal of Embryology & Stem Cell Research

4: Toll-Like Receptor2,4; GM-CSF: Granulocyte Monocyte- Colony Stimulating Factor; G-CSF: Granulocyte-Colony combination to IL-6 and IL-1 31]. secrete TGF-β leading to activation of macrophages in β [ Stimulating Factor; IGF: Insulin Growth Factor; HGF: cell phenotype as a result of microenvironment stimulation HepatocyteIntroduction Growth Factor. or byTherefore, an appropriate ADSCs can composition be differentiated of cell towards culture a desiredmedia. Indeed, ADSC’s functions are modulated by the composition Adipose derived stem cell (ADSC)-based therapy is very and the presence of immune cells of their microenvironment promising in treating damaged tissues and in completing full- and change their behavior in response to the nature of 32- the subcutaneous adipose tissue and have been reported to 36]. Their conditioned media has the ability to induce differentiatethickness skin into replacement. skin cells ensuringThese cells thus are skin identified regeneration within biomolecules,macrophages to cytokines secrete IL- or 10 cellular profile present [ and maintaining homeostasis [1-3]. Clinical applications cytokines, and at the other side to decrease the secretion of and28 ,37]. TNF anti-inflammatory adipose tissue. The capacity of these cells to proliferate and benefit from its simple and abundant collection from the pro-Also, inflammatory aging is anothercytokines parameter[ impacting the immunomodulation effect of ADSCs. Accumulation of self-renew in vitro as well as in vitro, added to their innate differentiation targeted more scientific advancements in the mostlyfield of by regenerative secreting a medicinepanel of cytokines [4,5]. Several and studieschemokines, have senescent cells 24result,38]. on an increase in the pro-inflammatory shown the ability of ADSC to act through cell-cell contact, but factors as IL-6, IL-8 and TNF-α associated to chronic cell proliferation, differentiation, homing and migration, inflammation [ senescencebeing involved and inapoptosis different [6-14]. biological These pathways mechanisms including are differentiateWe can considerinto skin thatcells, ADSCs to modulate are likely the theduration main of actor the involved in skin regeneration, their ability to self-renew, to implicated in the whole process of skin regeneration and dependent on the enrichment of their secretome and their woundTheir healing. immunomodulatory effects make them more inflammatory phase and the re-epithelialization is potentially suitable for use compared to their counterpart from bone 15]. These cells have been cellular network within skin layers. More investigations are used for many investigations and are largely used for graft however needed to better address their relative relationships improvementmarrow and in umbilical cosmetic blood remodeling [ to prevent fat necrosis withinADSCs their Interactionsmicroenvironment. in Tissue Repair [16-18]. ADSCs present great ability in migration leading to Increasing evidences implicated ADSCs in maintaining skin homeostasis at a cellular level through cell differentiation their rapid recruitment into wounded sites where process and at the paracrine level. During normal development, skin of cell differentiation towards various skin cell components regenerative capability is performed by the resident ADSCs occurred. ADSCs are reported to regulate inflammation and providing for cellular turn over during skin homeostasis participate to the phases of wound healing [3]. These cells and repair after injury [33]. Basal layer is the skin location gain more interest with their enriched extracellular vesicles proteinscontaining thus growth promoting factors, and cytokines, accelerating MicroRNA skin regeneration (miR) and for recruiting and sending mature differentiated cells [produce12-14,19 different-23]. amounts of the extracellular matrix (ECM) (keratinocytes)where these active to multipotentthe outer of stem epidermis. cells are responsibleThrough a hierarchic gradient, these stem cells induced epidermis layer This suggested that these cells represent a rich source of factors and are able to address their microenvironment to production of transient amplifying cells [39]. Epidermal cells includingregeneration ADSCs by ensuringand DF are self-renewal closely interacted and a continuously to maintain local microenvironment propitious for cell turnover leading modulate wound healing and tissue regeneration. to skin regeneration. Adding to their aptitude to differentiate 11 into keratinocytes, DF and probably melanocytes, crosstalk of (GDF11)Among, interleukin-6 the secreted (IL-6), growth IL-1 factors, transforming10, Toll like growthReceptor factors-β 2 (TLR2) (TGF-β), growth differentiation factor ECM secretion leaded to a physical environment critical for both involved in skin and different organsβ, IL-8, biology IL- [6,11,24- theADSCs maintenance and these cellsof the is stem a part cell of normalniche [40]. skin function where 27]. These factors target, TLR4 similar and TNF-αskin cells are including highlighted dermal and micro vascular endothelial cells [28-30]. Additionally, ADSCs the homeostasis of skin microenvironment by releasing fibroblast (DF), keratinocytes, melanocytes and dermal Moreover, ADSCs secrete exosomes to modulate

Mazini L, et al. Adipose derived stem cells (ADSCs) Immunomodulation Impact on Skin Copyright© Mazini L, et al. Tissue Repair. J Embryol Stem Cell Res 2020, 4(1): 000136. 3 Journal of Embryology & Stem Cell Research differentiation, cell proliferation and in migration [11,19,41- endothelial cells and macrophages migration occurred the43]. growth factors involving in neo-angiogenesis, cell probablyand amplifying once theafter growth macrophages factor secretion leaded implied. to secretion However, of the ECM proteins especially collagen I and III, elastin skin cell and especially DF has been provided by Hu et al Another proof of evidence of S2ADSCs interactions within angiogenesisand fibronectin [48,49]. and to activation of DF to proliferate and migrate. DF also secrete VEGF, TGF-β and b-FGF leading to where skin fibroblasts cell line H 7 was found to activate interactionsADSCs to differentiateof microvascular into endothelial fibroblast-like cells and cells ADSCs highly are alsoexpressing of great vimentin, interest in HSP47 skin cell and regeneration desmin mRNA and level proliferation [44]. The phaseThe through collagen inhibiting production ECM amplifieddegradation by by cross-talking increasing by providing IL-6, IL-8, monocyte chemoattractant protein-1 TIMPsbetween secretion ADSCs, and DF theirand bindingTGF-β would to MMPs facilitate [50]. Xiao, remodeling et al. have (MCP-1) reported that adipose tissue secretome increased N-cadherin regulation [45,46]. and VEGF leading to inflammation and angiogenesis The Secretome of ADSCs duringand CD44 ECM adhesion remodeling molecules [51]. involvedCombination in fibroblasts of activin motility B and during wound healing and stimulating fibronectin expression In normal conditions, ADSCs are continuously activated epithelialization through promoting keratinocytes and by human serum and platelets to induce their proliferation ADSCs leaded to rapid wound2] closure and to accelerating

fibroblasts proliferation [ . The αβ6 integrin exclusively and differentiation. Once the tissues are wounded, platelets repairexpressed [52] by epithelial cells, was associatedin vitr o,to ADSCs the induced stem cells to initiate the inflammatory phase by regeneration of basement membrane zone during wound secreting platelet- derived growth factor (PDGF), IL-6 and . When miming injured conditions [53] IL-8 which lead to migration of macrophages and neutrophils were indeed demonstrated to accelerate neovascularization ADSCsto the woundedadditionally site [47],secrete, and TGF-βprostaglandin inducing E2 induction (PGE2) of, through the expression of hypoxia- inducible factor-1α monocytes toDF11 macrophages. With similarity to platelets, by regulatingImmunoregulatory VEGF gene expression Effects ofin endothelialADSCs in Skin cells [54]. byTNF-α polarizing and G macrophages potentiating from M1 thus to theM2. proinflammatory Evidences of involvement of ADSCs in immunomodulation responses and later anti-inflammatory cytokines secretion DF11, ADSCs secrete other have suggested that these cells might play a crucial role in skinof tissues immunological and their functions presence in within physiologic the epidermal and injured layer (b-FGF),In addition stromal-derived to TGF-β and factor- G 1 (SDF-1), insulin-like skin. Accumulation of senescent cells in the skin is related growth factors such as basic- fibroblast Growth Factor 10 10b), IL6, Il-10, IL-1, TLR2, TLR4, G-CSF, growthGM-CSF factorand many (IGF), others. hepatocyte These factors growth are factor included (HGF) in andthe associatedto the production microenvironment of pro-inflammatory as in aged factors tissues such [55]. as IL-6,This winglessmechanisms b regulating(Wnt skin cell regeneration and repair IL-8, TNF-α thus changing the inflammatory profile of the [6,7,28] 1 24,38]. Microvascular skin inflamm-aging was also supported by highly secreted probably. Thethrough factors their VEGF, differentiation PDGF, TGF-β, into b-FGF endothelial and HGF increasepro-inflammatory secretion cytokineof IL-6, IL-IL-8, βMCP- [ 1 modulating skin progenitorpromoted new cells blood [6,48]. vessels The secreted during the GM-CSF proliferative can take phase, part endothelial cells while interacting with ADSCs lead to of this activation by inducing differentiation into committed monocytes potentially activated to macrophages and inflammationMigration [46]. of ADSCs to the injured site is of a pivotal endothelial cells.

theinterest, proliferation their immune and remodeling profile andphases their of healing potential [56-58]. shift a key role in skin tissue regeneration such as PDGF, IL-1, towards a more anti-inflammatory phenotype is required for BoneActually, Morphogenic other Proteincytokines (BMP) and 6,miR BMP9, are miR-expected21, miR- to play and miR-124 by targeting DF, keratinocytes and especially phaseThe cytokine and initiate profile the of proliferation T, B and dendritic and remodeling cells was influenced phases in immune cells [12,14]. 23a by ADSCs which lead to the interruption of the inflammatory

chronic wounds [59,60]. cytokines has improved ADSC’s responses to cancer and facilitateADSCs cell are migration expected and to angiogenesis participate by actively auto induction to ECM Preconditioning with inflammatory or pro-inflammatory production, whereby its abundant accumulation would inflammation in addition to the increase of their survival Mazini L, et al. Adipose derived stem cells (ADSCs) Immunomodulation Impact on Skin Copyright© Mazini L, et al. Tissue Repair. J Embryol Stem Cell Res 2020, 4(1): 000136. 4 Journal of Embryology & Stem Cell Research

[61-64]. Several reports are in favor of optimizing the 32] 1 and IL-6, this factor increases macrophages recruitment, and theirphases polarization of wound from healing M1 [to M. 2 Together [31] leading with to IL- a βphase implicationtherapeutic of benefit GDF11 of ADSCs as a result of the combined action of cytokines including TGF-β and TNF-α. The potential activation helps the secretion of ECM proteins involved in its highly stimulation of in DF disrupting and ADSCs the and pro-inflammatory by amplifying skinof secretion structure of repair, anti-inflammatory angiogenesis, cytokines cell proliferation [65,66]. Thisand status towards the anti-inflammatory one is likely due to migration and re-epithelialization (Figure 1) microenvironmentthe action of TGF-β mighton ADSCs be crucialproliferation in restoring and secretome. cellular . The αβ6 ageThis defects epigenetically and or increasing modification cell ability and regulation to differentiate of ADSC’s and skinintegrin and ADSCsecreted microenvironment by epithelial cells [52] was. Recently, reported the to collagenactivate migrate. TGF-β modulating thus the innate1 immuneprotein contributed surveillance to in healing process via increasing M2 macrophages recruitment triple helix repeat containing

TFG-β, secreted by ADSCs and other epithelial cells is and TGF-β expression level [67]. involved in the inflammatory, proliferative and remodeling

Figure 1: Immunomodulatory effects of ADSCs. Through their secretome, these cells change the macrophages polarization

thus re-epithelialization. and acquire an anti-inflammatory profile to enhance skin cell proliferation and migration, improve angiogenesis accelerating

Additionally, TNF-α DF11 cytokinesA recent by workimmune of Wang, cells etin al.vi tr[68]o and has shownin vivo thatin miceskin by GDF11 in atherosclerosis. was activated by NF-kB signaling treatment with rG decreased secretion of inflammatory pathway during inflammation reaction being suppressed The impact of microenvironment changing on models of psoriasis-associated inflammation, an DF11 extended ADSCs functionality, on their induction of proliferation, infiltration of immune cells sustaining skin inflammation. differentiation and migration has already been reported Suppression of severity of this inflammation by G was [32-35,72]. Reciprocally, ADSCs are reported to address macrophagesprovided by reducingactivation macrophages has been infiltration reported to thein skin this microenvironment in vitro, their conditioned media and inhibiting the NF- kB signaling pathway. Moreover, argued on the protective effect of GDF11 secretion of TNF and IL-10 autoimmune inflammatory diseases [69]. Other evidences64.7 was reported to activate macrophages and to increase the from inflammatory71]. anti-inflammatory cytokines reaction by inhibiting inflammatory responses in RAW2 stimulating thus wound healing [37,73]. macrophages probably by inhibiting TNF-α release [70, Mazini L, et al. Adipose derived stem cells (ADSCs) Immunomodulation Impact on Skin Copyright© Mazini L, et al. Tissue Repair. J Embryol Stem Cell Res 2020, 4(1): 000136. 5 Journal of Embryology & Stem Cell Research

Other results have demonstrated the suppression of macrophages lead to changes in the immunological phenotype Interactions between resident skin ADSCs and local2 T-cell proliferation and TNF-α secretion when ADSCs were preconditioned with inflammatory1 receptor media antagonist simultaneously and IL- theof both increase cells inwhich Treg is cell reflected activation by the[74]. differentiation ADSC’s changes of are M 1to0 [73]. the significantAnother interesting upregulation in vitro of study the anti-inflammatoryhas reported that anti-inflammatory profile, the suppression of Th cells and genes expression and the IL- inhibit the and involvedalso relevant in skin through homeostasis the secretion [29]. Adding of anti-inflammatory to their direct macrophages cultured with ADSCs have also the ability to skincytokines cell contact, and the these increase cells in orchestrate the expression and accelerate of genes Th2 Th17 cells and to increase significantly the mechanisms supporting their differentiation into DF mussel-the frequency inspired of Treg nanostructure cells as the samescaffold time derivedas adopting ADSCs the and keratinocytes, melanin production, neo-angiogenesis tohealing shift andmacrophages anti- inflammatory from M1 profileto M2 [74]. immunomodulatory Using a specific 2]. The reciprocal and increase in capillary density and finally the re- profile, to enhance vascularization thus accelerating wound suggestepithelialization that dermal and composition wound closure in ADSCs [3 and macrophages closure [64]. This result also suggests the crosstalk between interactions between ADSCs and macrophages32,7 let5]. usTheir to potentiatedADSCs and localby direct immune cell-cell cells contact to address [32,75]. the inflammatory status of their microenvironment which appear to be is the key regulator of the skin immune profile [ respective number would impact the inflammatory status of the skin and consequently skin cell regeneration and function At the same way, IL-6 the major pro-inflammatory1). Auto- in both normal and wounded conditions by modulating the componentsactivated ADSCs of ADSC’s amplify secretome their secretion was reported and stimulate to initiate the dependentfate of ADSCs on their [74]. dose Indeed, in an a animal recent model work [76]. has confirmed the inflammatory phaseR2, in TLR4, injured IL- tissues10 (Figure that the immunomodulatory effect of ADSCs is significantly and GDF11 secretion of TNF-α, TL , b-FGF, VEGF, TGF-β dependent of the number of cells injected their route of enhance angiogenesis,. These secretions cell migration would takeand proliferation.place to short and Moreover, the clinical efficacy of ADSCs remains shift the ADSCs profile to a less inflammatory profile and Conclusion administration and their location’s origin as well. Visceral [ADSCs72]. secrete higher quantities of inflammatory cytokines IL- in 6, IL-8 and TNF-α when compared to the subcutaneous one’s vitro in vitro, added to their innate differentiation The capacity of ADSCs to proliferate and self-renew factors lead to inherent variability relative to ADSCs viability, regenerativeas well asmedicine. In normal conditions and through Other point of view to consider is that patient-associated theirtargeted enriched more scientificsecretome, advancements these cells inorchestrate the field the of mechanisms related to cell differentiation, proliferation and Collectedself-renewal from ability, donors differentiation presenting medical potency histories and theirsuch cell migration even by upregulating genes involved in skin secretory profile containing immunomodulatory mediators. barrier function, in cellular proliferation and epidermal turnover and differentiation. Nevertheless, these regulations as breast cancer, Croh’n diseases or other inflammatory appear to be attained by their immunomodulating ability suggesteddiseases, ADSCs that thepresent in vitro an inflammation or in vivo preconditioninginduced secretome of associated to their self-renewal capacity [68,77]. This cell-to-cell contact. through their paracrine and autocrine pathways as well as ADSCs could open the way to potential new strategies for treating skin inflammations.

In wound defects, ADSCs migrate rapidly towards the This might be useful and should be considered when wounded sites where process of cell differentiation into designing new clinical therapies using ADSCs or their specific skin cell components occurs. However, ADSCs participate Acknowledgment:exosomes whereby their immunomodulation activities occur. agingmore senescent likely to allcells the increased phases and of woundthe paracrine healing senescent through University of Mohammed VI Polytechnic for funding this autocrine and paracrine pathways. Otherwise, during The authors wish to thank the secretome of ADSCs can trigger and reinforce inflammation considered the most immune cells involved in the innate work.Authors Contributions: All authors participated in the skinwithin immune their surveillance, microenvironment but recently [55]. as Macrophages the key regulator are

researchConflicts and of writing Interest: of this manuscript. of skin immunomodulation as they infiltrate skin layers in inflammation-associated diseases and during aging. The authors declare no conflict of Mazini L, et al. Adipose derived stem cells (ADSCs) Immunomodulation Impact on Skin Copyright© Mazini L, et al. Tissue Repair. J Embryol Stem Cell Res 2020, 4(1): 000136. 6 Journal of Embryology & Stem Cell Research interest.

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Mazini L, et al. Adipose derived stem cells (ADSCs) Immunomodulation Impact on Skin Copyright© Mazini L, et al. Tissue Repair. J Embryol Stem Cell Res 2020, 4(1): 000136.