International Journal of Molecular Sciences Review Applications of Mesenchymal Stem Cells in Skin Regeneration and Rejuvenation Hantae Jo 1,† , Sofia Brito 1,†, Byeong Mun Kwak 2,3,† , Sangkyu Park 4,* , Mi-Gi Lee 5,* and Bum-Ho Bin 1,4,* 1 Department of Applied Biotechnology, Ajou University, Suwon 16499, Korea; [email protected] (H.J.); sofi[email protected] (S.B.) 2 Department of Meridian and Acupoint, College of Korean Medicine, Semyung University, Chungbuk 27136, Korea; [email protected] 3 School of Cosmetic Science and Beauty Biotechnology, Semyung University, 65 Semyung-ro, Jecheon-si, Chungcheongbuk-do 27136, Korea 4 Department of Biological Sciences, Ajou University, Suwon 16499, Korea 5 Bio-Center, Gyeonggido Business and Science Accelerator, Suwon 16229, Korea * Correspondence: [email protected] (S.P.); [email protected] (M.-G.L.); [email protected] (B.-H.B.); Tel.: +82-31-219-2967 (S.P.); +82-31-888-6952 (M.-G.L.); +82-031-219-2816 (B.-H.B.) † These authors contributed equally to this study. Abstract: Mesenchymal stem cells (MSCs) are multipotent stem cells derived from adult stem cells. Primary MSCs can be obtained from diverse sources, including bone marrow, adipose tissue, and umbilical cord blood. Recently, MSCs have been recognized as therapeutic agents for skin regeneration and rejuvenation. The skin can be damaged by wounds, caused by cutting or breaking of the tissue, and burns. Moreover, skin aging is a process that occurs naturally but can be worsened by environmental pollution, exposure to ultraviolet radiation, alcohol consumption, tobacco use, and undernourishment. MSCs have healing capacities that can be applied in damaged and aged Citation: Jo, H.; Brito, S.; Kwak, B.M.; Park, S.; Lee, M.-G.; Bin, B.-H. skin. In skin regeneration, MSCs increase cell proliferation and neovascularization, and decrease Applications of Mesenchymal Stem inflammation in skin injury lesions. In skin rejuvenation, MSCs lead to production of collagen and Cells in Skin Regeneration and elastic fibers, inhibition of metalloproteinase activation, and promote protection from ultraviolet Rejuvenation. Int. J. Mol. Sci. 2021, 22, radiation-induced senescence. In this review, we focus on how MSCs and MSC-derived molecules 2410. https://doi.org/10.3390/ improve diseased and aged skin. Additionally, we emphasize that induced pluripotent stem cell ijms22052410 (iPSC)-derived MSCs are potentially advanced MSCs, which are suitable for cell therapy. Academic Editor: Sung-Chul Jung Keywords: mesenchymal stem cells; skin regeneration; wound healing; skin rejuvenation; antiaging; induced pluripotent stem cell Received: 19 January 2021 Accepted: 24 February 2021 Published: 27 February 2021 1. Mesenchymal Stem Cells Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Mesenchymal stem cells (MSCs) were observed for the first time in bone marrow published maps and institutional affil- by Cohnheim in 1867, who discovered that these cells could be the source of fibroblasts iations. involved in wound repair [1]. Later, MSCs were first isolated and cultured in 1968 by A. J. Friedenstein. Using cells prevenient from murine bone marrow, Friedenstein observed that transplanting cell colonies to semi-syngeneic animals could originate fibrous tissue, bone and bone containing bone marrow. However, only years after, it became clear that the works made by Friedenstein were due to cells with multipotent ability. The term Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. “mesenchymal stem cells” was presented by Caplan in 1991, after his studies with human This article is an open access article bone marrow research [2,3]. Since then, owing to their easy isolation, expansion, and distributed under the terms and multipotentiality, MSCs have been rapidly popularized as a promising therapeutic agent conditions of the Creative Commons for regenerative medicine. To date, it is a hot topic of research that is being explored for Attribution (CC BY) license (https:// multiple purposes. The International Society for Cellular Therapy (ISCT) has suggested creativecommons.org/licenses/by/ at least three conditions that can characterize MSCs. First, MSCs must adhere to a plastic 4.0/). culture vessel and grow. Second, MSCs should have CD73, CD90, and CD105 as cell surface Int. J. Mol. Sci. 2021, 22, 2410. https://doi.org/10.3390/ijms22052410 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 2410 2 of 18 Int. J. Mol. Sci. 2021, 22, 2410 2 of 19 culture vessel and grow. Second, MSCs should have CD73, CD90, and CD105 as cell sur- faceantigens. antigens. Also, Also, CD11b, CD11b, CD14, CD14, CD19, CD19, CD34, CD34, CD45, CD45, CD79 CD79α, andα, HLA-DR and HLA-DR antigens, antigens, which whichare hematopoietic are hematopoietic stem stem cell antigens, cell antigens, should should not existnot exist on MSCs.on MSCs. Third, Third, MSCs MSCs must must be beable able to to differentiate differentiate into into osteoblasts, osteoblasts, adipocytes, adipocytes, and and chondrocytes chondrocytesin vitroin vitro[4]. [4]. After After the thediscovery discovery of of bone bone marrow-derived marrow-derived MSCs MSCs (BM-MSCs), (BM-MSCs), several several otherother MSC sources sources have have beenbeen reported, reported, including including endometrium endometrium [5], [5], dental dental pulp pulp tissues tissues [6], [6], skeletal skeletal muscles muscles [7], [7], placentaplacenta [8], [8], adipose adipose tissue tissue [9], [9], umbilical umbilical cord cord blood blood [10], [10], and and Wharton’s Wharton’s jelly jelly [11] [11] are are sourcessources of of MSCs. MSCs. MSCs MSCs are are suitable suitable for for cell cell therapy therapy because: because: a) They (a) They have have stemness stemness po- tency;potency; b) They b) They are are easy easy to toisolate isolate from from original original tissues; tissues; c) (c) They They have have less less severe severe ethical ethical issuesissues as as compared compared to to embryonic embryonic stem stem cells cells (ESC); d) (d) Unlike Unlike induced induced pluripotent pluripotent stem stem cellscells (iPSC), (iPSC), they they carry carry a a lower lower risk risk of of teratoma-formation teratoma-formation [12,13]; [12,13]; and e) (e) They They are are useful useful forfor a a variety variety of of therapeutic therapeutic applications applications beca becauseuse of of their their ability ability to to migrate migrate to to damaged damaged tissuetissue by by chemoattraction chemoattraction [14]. [14]. Hence, Hence, it it is is possible possible to to apply apply MSCs MSCs for for the the treatment treatment of of tissuestissues of of different different origins origins [15–19]. [15–19]. TheThe skin skin is iscontinuously continuously exposed exposed to a to vari a varietyety of injuries. of injuries. In dermatology, In dermatology, MSCs MSCshave demonstratedhave demonstrated the potential the potential for skin for regenerati skin regenerationon in many in reported many reported cases [20,21]. cases [Addi-20,21]. tionally,Additionally, due to due the tomodern the modern population’s population’s increas increaseded esthetic esthetic standards, standards, the interest the interest in keep- in ingkeeping a youthful a youthful appearance appearance has also has alsoincreased. increased. Therefore, Therefore, skin skin rejuvenation rejuvenation using using MSCs MSCs is ais treatment a treatment that that attracts attracts attention attention [22–24]. [22–24 ].This This review review focuses focuses on on recent recent applications applications of of MSCsMSCs and and MSC-derived MSC-derived appendages appendages in in skin skin regeneration regeneration and and rejuvenation. rejuvenation. 2.2. Skin Skin Structure Structure TheThe various various layers ofof thethe skin skin have have distinct distinct structures structures and and functions functions that that work work together to- getherto protect to protect internal internal organs organs and serve and diverse serve di biologicalverse biological functions. functions. The skin The is composedskin is com- of posedthree majorof three layers: major epidermis, layers: epidermi dermis,s, anddermis, hypodermis and hypodermis (Figure1 ).(Figure 1). FigureFigure 1.1. SchematicSchematic representationrepresentation ofof thethe humanhuman skinskin structure.structure. TheThe epidermis, epidermis, the the outermost outermost layer, layer, plays plays a major a major defensive defensive role role[25]. [This25]. layer This layerpro- tectsprotects the skin the skinfrom fromdamage damage and stress, and stress, while whilealso limiting also limiting the passage the passage of water of and water chem- and icalchemical absorption absorption [26]. It is [26 constituted]. It is constituted predominantly predominantly of keratinocytes, of keratinocytes, which are present which arein thepresent epidermis in the in epidermis different inmaturation different maturationstates, constituting states, constituting around 95% around of the 95%layer of[27]. the Theselayer [cells27]. Theseproduce cells multiple produce keratins, multiple which keratins, are whichmajor arestructural major structuralproteins that proteins provide that strengthprovide to strength the skin to [28]. the skinThe [epidermis28]. The epidermis is subdivided is subdivided into five distinct into five strata: distinct stratum strata: corneum,stratum corneum, stratum lucidum, stratum lucidum, stratum granulosum, stratum granulosum, stratum stratumspinosum, spinosum, and stratum and stratum