INTRODUCTION

      The skin is the largest organ of the body. It is a key structure that protects internal tissues from mechanical damage, microbial infection, ultraviolet radiation, and extreme temperatures (Falanga, 2005; Ren et al., 2019; Rodrigues et al., 2019; Yang et al., 2020). In the United States, the annual medical cost of adverse wounds, including surgical incisions and scars, is $12 billion (Fife and Carter, 2012; Leavitt et al., 2016). Wound healing is a highly complex physiological regulation mechanism (Rodrigues et al., 2019) and a sophisticated multicellular process involving the coordination of various cell types and cytokines (Ho Jeong, 2010). Interactions involving epidermal and dermal cells, extracellular matrix (ECM), cytokines, and growth factors coordinate the entire repair process, which can be roughly divided into three stages: inflflammation, new tissue formation, and reconstruction (Heublein et al., 2015; Rodrigues et al., 2019). The inflflammatory stage includes neutrophil and monocyte recruitment and macrophage activation (Park and Barbul, 2004; Larouche et al., 2018). New tissue formation mainly refers to the proliferation, migration, and recombination of endothelial cells to form new blood vessels. When new blood vessels are formed, resident fifibroblasts proliferate and invade fifibrin clots to form contractile granulation tissue and produce collagen (Heng, 2011;Ansell and Izeta, 2015; Morikawa et al., 2019). This is followed by the proliferation of epidermal stem cells to rebuild the epidermis and stem cells from sebaceous glands, sweat glands, and hair follicles to form epidermal attachments.

Routine Treatment of Wounds

      In view of the complex, multi-stage, physiological and pathological processes of acute and chronic skin wound healing, effificient targeted wound healing treatment methods have been studied and applied. Thorough surgical debridement, prevention of infection, and elimination of dead spaces can minimize the risk of poor wound healing. Emerging technologies, such as those based on growth factors, bioactive molecules, and gene modifification, can also overcome the limitations of wound healing technology to some extent and serve as personalized therapeutic strategies (Tottoli et al., 2020).

      However, despite these efforts, existing interventions for wound healing have not been suffificiently effective. While there are several treatments available for both acute and chronic wounds, traditional approaches have had limited success. Due to the limitations of traditional methods, such as drug-based therapy, more effective treatments are needed. Skin regeneration therapy strategies and experimental techniques for cell and tissue engineering have also emerged. Stem cell-based therapy has opened a new door for wound repair and has attracted extensive attention in the fifield of regenerative medicine.

Stem Cells

      There are thousands of cells undergoing constant daily dynamic changes, such as loss and self-renewal, to maintain tissue homeostasis. Self-renewal is mainly driven by stem cells. Stimulation from regeneration signals, such as the accumulation of cross talk with niche factors or environmental changes at the time of injury, can disrupt tissue homeostasis, change stem cell behavior, induce self-renewal, and promote tissue growth (Hsu et al., 2011; Cosgrove et al., 2014; Porpiglia et al., 2017). When homeostasis is restored, differentiated progeny can return to their niche, preventing further proliferation and tissue regeneration, and this process is regulated by a careful balance of time-coordinated cell interactions and molecular feedback loops (Fuchs and Blau, 2020).

      Stem cells can be divided into embryonic and adult stem cells according to their developmental stage. Embryonic stem cells refer to cells derived from the embryonic inner cell mass or primordial germ cells in vitro. Embryonic stem cells have developmental totipotency and can differentiate into any type of cell. Embryonic stem cells can be extensively amplifified, screened, frozen, and resuspended in vitro without them losing their original characteristics (VanOudenhove et al., 2017; Wang et al., 2019; Sun et al., 2021). Adult stem cells, which are found in various tissues and organs of the body, are undifferentiated cells in a differentiated tissue that can selfrenew and differentiate into the specialized cells composing that tissue. These stem cells include hematopoietic stem cells, bone marrow mesenchymal stem cells, neural stem cells, muscle satellite cells, epidermal stem cells, and adipose stem cells (ASCs) (Cinat et al., 2021; Menche and Farin, 2021). In this review, we focus on ASCs.

Sources and Applications of ASCs

      Adipose tissue is a multifunctional tissue that contains a variety of cell types, such as the stromal vascular fraction and mature adipose cells. Stromal vascular fragments (SVFs) are a rich source of ASCs that can be easily isolated from human fat (Whiteside, 2008; O’Halloran et al., 2017). The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT MSC) proposes minimal criteria to defifine human MSC follows: First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. ASCs conform to most of the mesenchymal criteria of ISCT MSC, defifined as CD45− CD235a− CD31− CD34+ . The phenotype of cultured ASCs is CD13+ CD73+ CD90+ CD105+ CD31− CD45− CD235a− (Dominici et al., 2006; Bourin et al., 2013).

      ASCs have many advantages. They can be directly extracted from the adipose layer of a patient. Adipose tissue has a high frequency of stem cells, and ASCs can be used immediately with primary cells without the need for culture amplifification. In addition, ASCs provide not only cellular components, but also a large number of cytokines. Currently, ASCs have various clinical applications, including in scar reshaping and tissue repair, regeneration, and reconstruction, which are treatments often associated with cancer and metabolic diseases (Brayfifield et al., 2010; Gir et al., 2012; Rodrigues et al., 2014; Strong et al., 2015; Clevenger et al., 2016; Gentile and Garcovich, 2019; Sabol et al., 2019; Qin et al., 2020). Skin repair/regeneration is one of the most common clinical applications of ASCs, which has a positive therapeutic effect when used to treat skin wounds in patients with diabetes, vascular dysfunction, radiation history, or burn history Mechanism of ASCs in Wound Healing Factors Secreted by ASCs The mechanisms of wound healing by ASCs are complex and diverse. ASCs are involved throughout the entire process of wound healing, including inflflammation, proliferation, and remodeling (Hyldig et al., 2017). During inflflammation, ASCs may induce the transformation of the macrophage phenotype from pro-inflflammatory M1 to anti-inflflammatory M2 to regulate inflflammation (Lo Sicco et al., 2017). During proliferation and remodeling, ASCs secrete biological factors such as VEGF, HGF, IGF, PDGF, and TGF-β, which promote the proliferation and migration of fifibroblasts, the growth of new blood vessels, and the synthesis of collagen and other ECM proteins, which have benefificial effects on the skin (Rehman et al., 2004; Ho Jeong, 2010; Rodrigues et al., 2014; Na et al., 2017). For example, radiation damage to the skin can cause progressive occlusive endarteritis in local tissues, leading to severe tissue ischemia. Mesenchymal stem cells can be used to repair cellular damage and regenerate new blood vessels in ischemic tissues in patients with radioactive skin injury (Bensidhoum et al., 2005; François et al., 2006). ASC replacement after radiotherapy may reduce the incidence of radiation-related skin complications and is used for the prevention and treatment of skin injury related to tumor radiotherapy (Rigotti et al., 2007).

ASC-Derived Extracellular Vesicles

      Recent studies have shown that paracrine factors signifificantly promote the effect of stem cells during tissue repair and that extracellular vesicles may play an important role. Extracellular vesicles include exosomes and microvesicles, which play an important role in and are considered mediators of intercellular communication (Shao et al., 2018; Théry et al., 2018). The differences between exosomes and microvesicles in terms of physical function are yet to be clarifified. Microvesicles are large vesicles (50–1000 nm in diameter) that germinate outward from the plasma membrane, whereas exosomes are small vesicles (50–150 nm in diameter), and their secretion requires the fusion of multiple vesicles with the plasma membrane.

      In recent years, there has been extensive research on different types of cells, such as fifibroblasts, endothelial progenitor cells, and human umbilical cord mesenchymal stem cells, that are involved in tissue repair by regulating cell function and promoting angiogenesis and wound healing (Zhang et al., 2015a; Li et al., 2016; Geiger et al., 2015; Zhang et al., 2015b). ASC-derived exosomes have also been shown to accelerate wound healing by optimizing fifibroblast function (Figure 1) (Ren et al., 2019; Casado-Díaz et al., 2020). Studies have found that ASC-derived microvesicles (ASC-MVs) are easily internalized by human umbilical vein endothelial cells (HUVECs), HaCaTs, and fifibroblasts, suggesting that ASC-MVs can serve as a suitable vector for delivering a variety of biomolecules and signals to these targeted cells. ASC-MVs can enhance the migration and proliferation of HUVECs, HaCaTs, and fifibroblasts through internalization (Zhang et al., 2018; Bi et al., 2019; Ren et al., 2019). Cell cycle progression can be accelerated in a variety of ways, including by increasing the expression of genes related to cyclin D1, cyclin D2, cyclin A1, and cyclin A2, ultimately promoting wound healing (Bretones et al., 2015).

      The migration of HUVECs and angiogenesis play an important role in promoting wound healing. ASC-MVs can signifificantly upregulate the gene expression of integrin β1 and CXCL16 and regulate migration of HUVECs (Hattermann et al., 2008; Tang et al., 2017). ASC-MVs can also accelerate the wound healing process by promoting angiogenesis (Zhang et al., 2018).

ASCs Serve as Effective Immunomodulators in Inflflammatory Environments to Promote Wound Healing and Regeneration

      Adipose tissue has an immune function because it contains many immune cells and immunomodulatory cells, including ASCs. ASCs regulate mechanisms related to cell differentiation, proliferation, and migration through exosomes by upregulating genes involved in different functions, including skin barrier, immune regulation, cell proliferation, and epidermal regeneration (58). In addition, there are several populations of stromal and immune cells in heterogeneous products obtained after the digestion of adipose tissue, including SVFs. These properties make ASCs effective immune modulators in inflflammatory environments (DelaRosa et al., 2012; Gardin et al., 2018; Li and Guo, 2018).

      ADSCs directly interact with their microenvironment and specififically the immune cells, including macrophages, NK cell, T cells and B cells, resulting in differential inflflammatory and antiinflflammatory effect (Figure 2) (Mazini et al., 2021). The immune regulatory function of ASCs is manifested as regulation of the Th1/ Th2 balance and promotion of Tregs to restore immune tolerance. ASCs secrete the anti-inflflammatory cytokine interleukin-10 (IL- 10), which enhances Treg activity, and Tregs respond by further secreting IL-10 and amplifying IL-10 signaling (Chaudhry et al., 2011). Tregs and IL-10 attenuate Th1 and Th17 activity, thereby reducing the aggregation of additional pro-inflflammatory immune cells at pathological sites (Skapenko et al., 2005; Chaudhry et al., 2011). Additionally, the low expression of NK-activated receptor ligands increases human ASC resistance to NK-mediated recognition, which enables them to remain in the host for longer period. Furthermore, the mechanism by which human ASCs develop NK cell tolerance may be mediated by soluble factors (Spaggiari et al., 2008; DelaRosa et al., 2012). The role of these anti-inflflammatory and immunomodulatory effects of ASCs in wound healing needs to be further confifirmed.

DISCUSSION

      Although ASCs are fundamental to the tissue regeneration process, the clinical transformation of ASC-based therapies remains problematic. Due to the variation in donor age, sex, body mass index, clinical condition, and cell sampling location, ASCs are heterogeneous. Transplanted cells in severe trauma cases have only a limited ability to survive, which can affect their phenotypic features and functions, including proliferation, differentiation potential, immune phenotype, and paracrine activity (Prieto González, 2019). Therefore, future studies on the role of ASCs in regenerative medicine, especially dermatology, are still needed. Nevertheless, ASCs have promising applications in regenerative medicine, including the development of lipogenic potential and the construction of artifificial skin by replacing dermal fifibroblasts (Trottier et al., 2008; Tartarini and Mele, 2015), which will be the direction of our future research.

AUTHOR CONTRIBUTIONS

      All authors contributed to the design of the study and writing of the manuscript. NZ and HC undertook the research, YW and HC wrote the main manuscript text and prepared fifigures. ZL revised the article critically for important intellectual content and fifinal approval of the version to be submitted. All authors reviewed the manuscript.

REFERENCES

1.Ansell, D. M., and Izeta, A. (2015). Pericytes in Wound Healing: Friend or Foe? Exp. Dermatol. 24 (11), 833–834. doi:10.1111/exd.12782

2.Barrientos, S., Stojadinovic, O., Golinko, M. S., Brem, H., and Tomic-Canic, M.(2008). PERSPECTIVE ARTICLE: Growth Factors and Cytokines in Wound healing. Wound Repair Regen. 16 (5), 585–601. doi:10.1111/j.1524- 475X.2008.00410.x

3.Bensidhoum, M., Gobin, S., Chapel, A., Lemaitre, G., Bouet, S., Waksman, G., et al.(2005). Potentiel thérapeutique des cellules souches mésenchymateuses humaines dans les lésions cutanées radioinduites. J. Soc. Biol. 199 (4), 337–341. doi:10.1051/jbio:2005035

4.Bi, H., Li, H., Zhang, C., Mao, Y., Nie, F., Xing, Y., et al. (2019). Stromal Vascular Fraction Promotes Migration of Fibroblasts and Angiogenesis Through Regulation of Extracellular Matrix in the Skin Wound Healing Process. Stem Cel Res Ther 10 (1), 302. doi:10.1186/s13287-019-1415-6

5.Bourin, P., Bunnell, B. A., Casteilla, L., Dominici, M., Katz, A. J., March, K. L., et al. (2013). Stromal Cells from the Adipose Tissue-Derived Stromal Vascular Fraction and Culture Expanded Adipose Tissue-Derived Stromal/stem Cells: A Joint Statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 15 (6), 641–648. doi:10.1016/j.jcyt.2013.02.006

6.Brayfifield, C., Marra, K., and Rubin, J. P. (2010). Adipose Stem Cells for Soft Tissue Regeneration. Handchir Mikrochir Plast. Chir 42 (2), 124–128. doi:10.1055/s- 0030-1248269

7.Bretones, G., Delgado, M. D., and León, J. (2015). Myc and Cell Cycle Control. Biochim. Biophys. Acta (Bba) - Gene Regul. Mech. 1849 (5), 506–516. doi:10.1016/j.bbagrm.2014.03.013

8.Casado-Díaz, A., Quesada-Gómez, J. M., and Dorado, G. (2020). Extracellular Vesicles Derived from Mesenchymal Stem Cells (MSC) in Regenerative Medicine: Applications in Skin Wound Healing. Front. Bioeng. Biotechnol. 8, 146. doi:10.3389/fbioe.2020.00146

9.Chaudhry, A., Samstein, R. M., Treuting, P., Liang, Y., Pils, M. C., Heinrich, J.-M., et al. (2011). Interleukin-10 Signaling in Regulatory T Cells Is Required for Suppression of Th17 Cell-Mediated Inflflammation. Immunity 34 (4), 566–578. doi:10.1016/j.immuni.2011.03.018

10.Cinat, D., Coppes, R. P., and Barazzuol, L. (2021). DNA Damage-Induced Inflflammatory Microenvironment and Adult Stem Cell Response. Front. Cel Dev. Biol. 9, 729136. doi:10.3389/fcell.2021.729136

Clevenger, T. N., Luna, G., Fisher, S. K., and Clegg, D. O. (2016). Strategies for

11.Bioengineered Scaffolds That Support Adipose Stem Cells in Regenerative Therapies. Regenerative Med. 11 (6), 589–599. doi:10.2217/rme-2016-0064

12.Cosgrove, B. D., Gilbert, P. M., Porpiglia, E., Mourkioti, F., Lee, S. P., Corbel, S. Y., et al. (2014). Rejuvenation of the Muscle Stem Cell Population Restores Strength to Injured Aged Muscles. Nat. Med. 20 (3), 255–264. doi:10.1038/ nm.3464

13.DelaRosa, O., Sánchez-Correa, B., Morgado, S., Ramírez, C., del Río, B., Menta, R., et al. (2012). Human Adipose-Derived Stem Cells Impair Natural Killer Cell Function and Exhibit Low Susceptibility to Natural Killer-Mediated Lysis. Stem Cell Dev. 21 (8), 1333–1343. doi:10.1089/scd.2011.0139

14.Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F. C., Krause, D. S., et al. (2006). Minimal Criteria for Defifining Multipotent Mesenchymal Stromal Cells. The International Society for Cellular Therapy Position statement. Cytotherapy 8 (4), 315–317. doi:10.1080/14653240600855905

15.Falanga, V. (2005). Wound Healing and its Impairment in the Diabetic Foot. The Lancet 366 (9498), 1736–1743. doi:10.1016/S0140-6736(05)67700-8

16.Fife, C. E., and Carter, M. J. (2012). Wound Care Outcomes and Associated Cost Among Patients Treated in US Outpatient Wound Centers: Data from the US Wound Registry. Wounds 24 (1), 10–17.

17.François, S., Mouiseddine, M., Mathieu, N., Semont, A., Monti, P., Dudoignon, N., et al. (2006). Human Mesenchymal Stem Cells Favour Healing of the Cutaneous Radiation Syndrome in a Xenogenic Transplant Model. Ann. Hematol. 86 (1), 1–8. doi:10.1007/s00277-006-0166-5

18.Fuchs, E., and Blau, H. M. (2020). Tissue Stem Cells: Architects of Their Niches. Cell Stem Cell 27 (4), 532–556. doi:10.1016/j.stem.2020.09.011

19.Gardin, C., Ferroni, L., Bellin, G., Rubini, G., Barosio, S., and Zavan, B. (2018).Therapeutic Potential of Autologous Adipose-Derived Stem Cells for the Treatment of Liver Disease. Int. J. Mol. Sci. 19 (12), 4064. doi:10.3390/ ijms19124064

20.Geiger, A., Walker, A., and Nissen, E. (2015). Human Fibrocyte-Derived Exosomes Accelerate Wound Healing in Genetically Diabetic Mice. Biochem. Biophysical Res. Commun. 467 (2), 303–309. doi:10.1016/j.bbrc.2015.09.166

21.Gentile, P., and Garcovich, S. (2019). Concise Review: Adipose-Derived Stem Cells (ASCs) and Adipocyte-Secreted Exosomal microRNA (A-SE-miR) Modulate Cancer Growth and proMote Wound Repair. J. Clin. Med. 8 (6), 855. doi:10.3390/jcm8060855

22.Gir, P., Oni, G., Brown, S. A., Mojallal, A., and Rohrich, R. J. (2012). Human Adipose Stem Cells. Plast. Reconstr. Surg. 129 (6), 1277–1290. doi:10.1097/PRS.0b013e31824ecae6

23.Hattermann, K., Ludwig, A., Gieselmann, V., Held-Feindt, J., and Mentlein, R. (2008). The Chemokine CXCL16 Induces Migration and Invasion of Glial Precursor Cells via its Receptor CXCR6. Mol. Cell Neurosci. 39 (1), 133–141. doi:10.1016/j.mcn.2008.03.009

24.Heng, M. C. Y. (2011). Wound Healing in Adult Skin: Aiming for Perfect Regeneration. Int. J. Dermatol. 50 (9), 1058–1066. doi:10.1111/j.1365- 4632.2011.04940.x

25.Heublein, H., Bader, A., and Giri, S. (2015). Preclinical and Clinical Evidence for Stem Cell Therapies as Treatment for Diabetic Wounds. Drug Discov. Today 20 (6), 703–717. doi:10.1016/j.drudis.2015.01.005

26.Ho Jeong, J. (2010). Adipose Stem Cells and Skin Repair. Curr. Stem Cel Res. 5 (2), 137–140. doi:10.2174/157488810791268690

27.Hsu, Y.-C., Pasolli, H. A., and Fuchs, E. (2011). Dynamics Between Stem Cells, Niche, and Progeny in the Hair Follicle. Cell 144 (1), 92–105. doi:10.1016/j.cell.2010.11.049

28.Hyldig, K., Riis, S., Pennisi, C., Zachar, V., and Fink, T. (2017). Implications of Extracellular Matrix Production by Adipose Tissue-Derived Stem Cells for Development of Wound Healing Therapies. Int. J. Mol. Sci. 18 (6), 1167. doi:10.3390/ijms18061167

29.Larouche, J., Sheoran, S., Maruyama, K., and Martino, M. M. (2018). Immune Regulation of Skin Wound Healing: Mechanisms and Novel Therapeutic Targets. Adv. Wound Care 7 (7), 209–231. doi:10.1089/wound.2017.0761

30.Leavitt, T., Hu, M. S., Marshall, C. D., Barnes, L. A., Lorenz, H. P., and Longaker, M. T. (2016). Scarless Wound Healing: Finding the Right Cells and Signals. Cell Tissue Res 365 (3), 483–493. doi:10.1007/s00441-016-2424-8

31.Li, P., and Guo, X. (2018). A Review: Therapeutic Potential of Adipose-Derived Stem Cells in Cutaneous Wound Healing and Regeneration. Stem Cel Res Ther 9 (1), 302. doi:10.1186/s13287-018-1044-5

32.Li, X., Jiang, C., and Zhao, J. (2016). Human Endothelial Progenitor Cells-Derived Exosomes Accelerate Cutaneous Wound Healing in Diabetic Rats by Promoting Endothelial Function. J. Diabetes its Complications 30 (6), 986–992. doi:10.1016/j.jdiacomp.2016.05.009

33.Lo Sicco, C., Reverberi, D., Balbi, C., Ulivi, V., Principi, E., Pascucci, L., et al. (2017). Mesenchymal Stem Cell-Derived Extracellular Vesicles as Mediators of Antiinflflammatory Effects: Endorsement of Macrophage Polarization. STEM CELLS Translational Med. 6 (3), 1018–1028. doi:10.1002/sctm.16-0363

34.Lozito, T. P., Jackson, W. M., Nesti, L. J., and Tuan, R. S. (2014). Human Mesenchymal Stem Cells Generate a Distinct Pericellular Zone of MMP Activities via Binding of MMPs and Secretion of High Levels of TIMPs. Matrix Biol. 34, 132–143. doi:10.1016/j.matbio.2013.10.003

35.Mazini, L., Rochette, L., Hamdan, Y., and Malka, G. (2021). Skin Immunomodulation During Regeneration: Emerging New Targets. J. Personalized Med. 11 (2), 85. doi:10.3390/jpm11020085

36.Menche, C., and Farin, H. F. (2021). Strategies for Genetic Manipulation of Adult Stem Cell-Derived Organoids. Exp. Mol. Med. 53 (10), 1483–1494. doi:10.1038/ s12276-021-00609-8

37.Morikawa, S., Iribar, H., Gutiérrez-Rivera, A., Ezaki, T., and Izeta, A. (2019). Pericytes in Cutaneous Wound Healing. Adv. Exp. Med. Biol. 1147, 1–63. doi:10.1007/978-3-030-16908-4_1

38.Na, Y. K., Ban, J.-J., Lee, M., Im, W., and Kim, M. (2017). Wound Healing Potential of Adipose Tissue Stem Cell Extract. Biochem. Biophysical Res. Commun. 485 (1), 30–34. doi:10.1016/j.bbrc.2017.01.103

39.O’Halloran, N., Courtney, D., Kerin, M. J., and Lowery, A. J. (2017). AdiposeDerived Stem Cells in Novel Approaches to Breast Reconstruction: Their Suitability for Tissue Engineering and Oncological Safety. Breast Cance(Auckl) 11, 117822341772677. doi:10.1177/1178223417726777

40.Park, J. E., and Barbul, A. (2004). Understanding the Role of Immune Regulation in Wound Healing. Am. J. Surg. 187 (5A), 11S–16S. doi:10.1016/S0002-9610(03) 00296-4

41.Porpiglia, E., Samusik, N., Ho, A. T. V., Cosgrove, B. D., Mai, T., Davis, K. L., et al.(2017). High-resolution Myogenic Lineage Mapping by Single-Cell Mass Cytometry. Nat. Cel Biol 19 (5), 558–567. doi:10.1038/ncb3507 Prieto González, E. A. (2019). Heterogeneity in Adipose Stem Cells. Adv. Exp. Med Biol. 1123, 119–150. doi:10.1007/978-3-030-11096-3_8

42.Qin, F., Huang, J., Zhang, W., Zhang, M., Li, Z., Si, L., et al. (2020). The Paracrine Effect of Adipose-Derived Stem Cells Orchestrates Competition Between Different Damaged Dermal Fibroblasts to Repair UVB-Induced Skin Aging. Stem Cell Int. 2020, 1–19. doi:10.1155/2020/8878370

43.Rehman, J., Traktuev, D., Li, J., Merfeld-Clauss, S., Temm-Grove, C. J., Bovenkerk, J. E., et al. (2004). Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells. Circulation 109 (10), 1292–1298. doi:10.1161/ 01.CIR.0000121425.42966.F1

44.Ren, S., Chen, J., Duscher, D., Liu, Y., Guo, G., Kang, Y., et al. (2019). Microvesicles from Human Adipose Stem Cells Promote Wound Healing by Optimizing Cellular Functions via AKT and ERK Signaling Pathways. Stem Cel Res Ther 10 (1), 47. doi:10.1186/s13287-019-1152-x

45.Rigotti, G., Marchi, A., Gali, M., Baroni, G., Benati, D., Krampera, M., et al. (2007). Clinical Treatment of Radiotherapy Tissue Damage by Lipoaspirate Transplant: A Healing Process Mediated by Adipose-Derived Adult Stem Cells. Plast. Reconstr. Surg. 119 (5), 1409–1422. doi:10.1097/01.prs.0000256047.47909.71

46.Riis, S., Newman, R., Ipek, H., Andersen, J. I., Kuninger, D., Boucher, S., et al. (2017). Hypoxia Enhances the Wound-Healing Potential of Adipose-Derived Stem Cells in a Novel Human Primary Keratinocyte-Based Scratch Assay. Int. J. Mol. Med. 39 (3), 587–594. doi:10.3892/ijmm.2017.2886

47.Rodrigues, C., de Assis, A. M., Moura, D. J., Halmenschlager, G., Saffifi, J., Xavier, L. L., et al. (2014). New Therapy of Skin Repair Combining Adipose-Derived Mesenchymal Stem Cells with Sodium Carboxymethylcellulose Scaffold in a Preclinical Rat Model. PLoS One 9 (5), e96241. doi:10.1371/journal.pone.0096241

48.Rodrigues, M., Kosaric, N., Bonham, C. A., and Gurtner, G. C. (2019). Wound Healing: A Cellular Perspective. Physiol. Rev. 99 (1), 665–706. doi:10.1152/ physrev.00067.2017

49.Sabol, R. A., Giacomelli, P., Beighley, A., and Bunnell, B. A. (2019). Adipose Stem Cells and Cancer: Concise Review. Stem Cells 37 (10), 1261–1266. doi:10.1002/stem.3050

50.Shao, H., Im, H., Castro, C. M., Breakefifield, X., Weissleder, R., and Lee, H. (2018). New Technologies for Analysis of Extracellular Vesicles. Chem. Rev. 118 (4), 1917–1950. doi:10.1021/acs.chemrev.7b00534

51.Skapenko, A., Leipe, J., Lipsky, P. E., and Schulze-Koops, H. (2005). The Role of the T Cell in Autoimmune Inflflammation. Arthritis Res. Ther. 7 (Suppl. 2), S4–S14. doi:10.1186/ar1703

52.Spaggiari, G. M., Capobianco, A., Abdelrazik, H., Becchetti, F., Mingari, M. C., and Moretta, L. (2008). Mesenchymal Stem Cells Inhibit Natural Killer-Cell Proliferation, Cytotoxicity, and Cytokine Production: Role of Indoleamine 2,3-dioxygenase and Prostaglandin E2. Blood 111 (3), 1327–1333. doi:10.1182/blood-2007-02-074997

53.Strong, A. L., Burow, M. E., Gimble, J. M., and Bunnell, B. A. (2015). Concise Review: The Obesity Cancer Paradigm: Exploration of the Interactions and Crosstalk with Adipose Stem Cells. Stem Cells 33 (2), 318–326. doi:10.1002/stem.1857

54.Sun, L., Fu, X., Ma, G., and Hutchins, A. P. (2021). Chromatin and Epigenetic Rearrangements in Embryonic Stem Cell Fate Transitions. Front. Cel Dev. Biol. 9, 637309. doi:10.3389/fcell.2021.637309

55.Tang, D., Yan, T., Zhang, J., Jiang, X., Zhang, D., and Huang, Y. (2017). Notch1 Signaling Contributes to Hypoxia-Induced High Expression of Integrin β1 in Keratinocyte Migration. Sci. Rep. 7, 43926. doi:10.1038/srep43926

56.Tartarini, D., and Mele, E. (2015). Adult Stem Cell Therapies for Wound Healing: Biomaterials and Computational Models. Front. Bioeng. Biotechnol. 3, 206. doi:10.3389/fbioe.2015.00206

57.Théry, C., Witwer, K. W., Aikawa, E., Alcaraz, M. J., Anderson, J. D., Andriantsitohaina, R., et al. (2018). Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV2018): A Position Statement of the International Society for Extracellular Vesicles and Update of the MISEV2014 Guidelines. J. Extracell Vesicles 7 (1), 1535750. doi:10.1080/ 20013078.2018.1535750

58.Tottoli, E. M., Dorati, R., Genta, I., Chiesa, E., Pisani, S., and Conti, B. (2020). Skin Wound Healing Process and New Emerging Technologies for Skin Wound Care and Regeneration. Pharmaceutics 12 (8), 735. doi:10.3390/ pharmaceutics12080735

59.Trottier, V., Marceau-Fortier, G., Germain, L., Vincent, C., and Fradette, J. (2008). IFATS Collection: Using Human Adipose-Derived Stem/Stromal Cells for the Production of New Skin Substitutes. Stem Cells 26 (10), 2713–2723. doi:10.1634/stemcells.2008-0031

60.VanOudenhove, J. J., Grandy, R. A., Ghule, P. N., Lian, J. B., Stein, J. L., Zaidi, S. K., et al. (2017). Unique Regulatory Mechanisms for the Human Embryonic Stem Cell Cycle. J. Cel. Physiol. 232 (6), 1254–1257. doi:10.1002/jcp.25567

61.Wang, D., Bu, F., and Zhang, W. (2019). The Role of Ubiquitination in Regulating Embryonic Stem Cell Maintenance and Cancer Development. Int. J. Mol. Sci. 20 (11), 2667. doi:10.3390/ijms20112667

62.Whiteside, T. L. (2008). The Tumor Microenvironment and its Role in Promoting Tumor Growth. Oncogene 27 (45), 5904–5912. doi:10.1038/onc.2008.271

63.Yang, S., Gu, Z., Lu, C., Zhang, T., Guo, X., Xue, G., et al. (2020). Neutrophil Extracellular Traps Are Markers of Wound Healing Impairment in Patients with Diabetic Foot Ulcers Treated in a Multidisciplinary Setting. Adv. Wound Care 9 (1), 16–27. doi:10.1089/wound.2019.0943

64.Zhang, B., Wang, M., Gong, A., Zhang, X., Wu, X., Zhu, Y., et al. (2015). HucMSCExosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing. Stem Cells 33 (7), 2158–2168. doi:10.1002/stem.1771

65.Zhang, J., Guan, J., Niu, X., Hu, G., Guo, S., Li, Q., et al. (2015). Exosomes Released from Human Induced Pluripotent Stem Cells-Derived MSCs Facilitate Cutaneous Wound Healing by Promoting Collagen Synthesis and Angiogenesis. J. Transl Med. 13, 49. doi:10.1186/s12967-015-0417-0

66.Zhang, W., Bai, X., Zhao, B., Li, Y., Zhang, Y., Li, Z., et al. (2018). Cell-free Therapy Based on Adipose Tissue Stem Cell-Derived Exosomes Promotes Wound Healing via the PI3K/Akt Signaling Pathway. Exp. Cel Res. 370 (2), 333–342. doi:10.1016/j.yexcr.2018.06.035

This document is transferred from Ning Zeng† , Hongbo Chen† , Yiping Wu and Zeming Liu *Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China