Advertisement

LPS-pretreatment adipose-derived mesenchymal stromal cells promote wound healing in diabetic rats by improving angiogenesis

  • Author Footnotes
    # Kuixiang Wang and Ziying Chen contributed equally to this study and shared the first authorship.
    Kuixiang Wang
    Footnotes
    # Kuixiang Wang and Ziying Chen contributed equally to this study and shared the first authorship.
    Affiliations
    Department of Orthopaedics, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
    Search for articles by this author
  • Author Footnotes
    # Kuixiang Wang and Ziying Chen contributed equally to this study and shared the first authorship.
    Ziying Chen
    Footnotes
    # Kuixiang Wang and Ziying Chen contributed equally to this study and shared the first authorship.
    Affiliations
    Department of Endocrinology, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
    Search for articles by this author
  • Liang Jin
    Affiliations
    Department of Hand and Foot Surgery, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
    Search for articles by this author
  • Lili Zhao
    Affiliations
    Department of Orthopaedics, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
    Search for articles by this author
  • Libin Meng
    Affiliations
    Department of Orthopaedics, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
    Search for articles by this author
  • Fanting Kong
    Affiliations
    Department of Oncology Surgery, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
    Search for articles by this author
  • Chenxin He
    Affiliations
    Department of Endocrinology, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
    Search for articles by this author
  • Fanlei Kong
    Affiliations
    Department of Orthopaedics, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
    Search for articles by this author
  • Lingtao Zheng
    Affiliations
    Department of Endocrinology, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
    Search for articles by this author
  • Fang Liang
    Correspondence
    Corresponding author.
    Affiliations
    Department of Endocrinology, Xingtai People's Hospital of Hebei Medical University, Xingtai 054000, Hebei Province, China
    Search for articles by this author
  • Author Footnotes
    # Kuixiang Wang and Ziying Chen contributed equally to this study and shared the first authorship.
Published:September 24, 2022DOI:https://doi.org/10.1016/j.injury.2022.09.041

      Abstract

      Mesenchymal stem cells (MSCs) play a key role in wound healing, and the advantages of pretreated MSCs in wound healing have previously been reported. In the present study, we investigated the impact of LPS pretreated human adipose-derived MSCs on skin wound healing in diabetic rats. We found that some improvements occurred through improving angiogenesis. Then, we scrutinized the impact of lipopolysaccharide (LPS) treatment on human adipose-derived MSCs in a high-glucose (HG) medium, as an in vitro diabetic model. In vivo findings revealed significant improvements in epithelialization and angiogenesis of diabetic wounds which received LPS pre-MSCs. Particularly, LPS pre-MSCs-treated diabetic wounds reached considerably higher percentages of wound closure. Also, the granulation tissue of these wounds had higher pronounced epithelialization and more vascularization compared with PBS-treated and MSCs-treated diabetic ones by CD31, VEGF, CD90, collagen 1, and collagen 3 immunostaining. Western-blots analyses indicated that LPS pre-MSCs led to the upregulation of vascular endothelial growth factor (VEGF) and DNMT1. In addition, significantly higher cell viability (proliferation/colonie), and elevated VEGF and DNMT1 protein expression were observed when MSCs were treated with LPS (10 ng/ml, 6 h) in HG culture media. Based on these findings, it is suggested that LPS pre-MSCs could promote wound repair and skin regeneration, in some major processes, via the improvement of cellular behaviors of MSCs in the diabetic microenvironment. The beneficial advantages of LPS treated with mesenchymal stem cells on wound healing may lead to establishing a novel approach as an alternative therapeutic procedure to cure chronic wounds in diabetic conditions.

      Keywords

      Abbreviations:

      MSCs (Mesenchymal stem cells), LPS (Lipopolysaccharide), DNMT1 (DNA methyl transferase 1), HG (high-glucose), VEGF (Vascular endothelial growth factor), ECM (Extracellular matrix), HGF (Hepatocyte growth factor), bFGF (basic fibroblast growth factor), TGF-β (Transforminggrowthfactor-β), IGF-1 (Insulin-like growth factor 1)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Injury
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kathawala Mustafa Hussain
        • Ng Wei Long
        • Liu Dan
        • Naing May Win
        • Yeong Wai Yee
        • Spiller Kara L
        • et al.
        Healing of chronic wounds: an update of recent developments and future possibilities.
        Tissue Eng Part B Rev. 2019; 25: 429-444https://doi.org/10.1089/ten.TEB.2019.0019
        • Mansbridge Jonathan
        Skin tissue engineering.
        J Biomater Sci Polym editor. 2008; 19: 955-968https://doi.org/10.1163/156856208784909417
        • DiPietro Luisa A
        Angiogenesis and wound repair: when enough is enough.
        J Leukoc Biol. 2016; 100: 979-984https://doi.org/10.1189/jlb.4MR0316-102R
        • Mazini Loubna
        • Rochette Luc
        • Admou Brahim
        • Amal Said
        • Malka Gabriel
        Hopes and limits of adipose-derived stem cells (ADSCs) and mesenchymal stem cells (MSCs) in wound healing.
        Int J Mol Sci. 2020; 21: 1306https://doi.org/10.3390/ijms21041306
        • Barman Pijus K
        • Koh Timothy J
        Macrophage dysregulation and impaired skin wound healing in diabetes.
        Front Cell Dev Biol. 2020; 8: 528https://doi.org/10.3389/fcell.2020.00528
        • Campbell Andrew
        • Brieva Thomas
        • Raviv Lior
        • Rowley Jon
        • Niss Knut
        • Brandwein Harvey
        • et al.
        Concise review: process development considerations for cell therapy.
        Stem Cells Transl Med. 2015; 4: 1155-1163https://doi.org/10.5966/sctm.2014-0294
        • Kang Hyeon Tae
        • Jang Kiseok
        • Jun Dae Won
        • Yoon Eileen L
        • Lee Seung Min
        • Saeed Waqar Khalid
        • et al.
        Macro-encapsulation of mesenchymal stem cells in acute and chronic liver injury animal models.
        J Gastroenterol Hepatol. 2021; 36: 1997-2007https://doi.org/10.1111/jgh.15434
        • Jimi S.
        • Takagi S.
        • De Francesco F.
        • Miyazaki M.
        • Saparov A.
        Acceleration of skin wound-healing reactions by autologous micrograft tissue suspension.
        Medicina (Kaunas). 2020; 56: 321https://doi.org/10.3390/medicina56070321
        • Jimi S.
        • Kimura M.
        • De Francesco F.
        • Riccio M.
        • Hara S.
        • Ohjimi H.
        Acceleration Mechanisms of Skin Wound Healing by Autologous Micrograft in Mice.
        Int J Mol Sci. 2017; 18: 1675https://doi.org/10.3390/ijms18081675
        • De Francesco F.
        • Graziano A.
        • Trovato L.
        • Ceccarelli G.
        • Romano M.
        • Marcarelli M.
        • et al.
        A regenerative approach with dermal micrografts in the treatment of chronic ulcers.
        Stem Cell Rev Rep. 2017; 13: 139-148https://doi.org/10.1007/s12015-016-9692-2
        • Francesco Francesco De
        • Gravina Pasquale
        • Busato Alice
        • Farinelli Luca
        • Soranzo Carlo
        • Vidal Luis
        • et al.
        Stem cells in autologous microfragmented adipose tissue: current perspectives in osteoarthritis disease.
        Int J Mol Sci. 2021; 22: 10197https://doi.org/10.3390/ijms221910197
        • Fu Xiaorong
        • Liu Ge
        • Halim Alexander
        • Ju Yang
        • Luo Qing
        And Guanbin Song. Mesenchymal stem cell migration and tissue repair.
        Cells. 2019; 8: 784https://doi.org/10.3390/cells8080784
        • Yu Songyan
        • Cheng Yu
        • Zhang Linxi
        • Yin Yaqi
        • Xue Jing
        • Li Bing
        • et al.
        Treatment with adipose tissue-derived mesenchymal stem cells exerts anti-diabetic effects, improves long-term complications, and attenuates inflammation in type 2 diabetic rats.
        Stem Cell Res Ther. 2019; 10: 333https://doi.org/10.1186/s13287-019-1474-8
        • Cheng Kang
        • Rai Partab
        • Plagov Andrei
        • Lan Xiqian
        • Kumar Dileep
        • Salhan Divya
        • et al.
        Transplantation of bone marrow-derived MSCs improves cisplatinum-induced renal injury through paracrine mechanisms.
        Exp Mol Pathol. 2013; 94: 466-473https://doi.org/10.1016/j.yexmp.2013.03.002
        • Jo Hantae
        • Brito Sofia
        • Kwak Byeong Mun
        • Park Sangkyu
        • Lee Mi-Gi
        • Bin Bum-Ho
        • et al.
        Applications of mesenchymal stem cells in skin regeneration and rejuvenation.
        int J Mol Sci. 2021; 22: 2410https://doi.org/10.3390/ijms22052410
        • Arabpour Maedeh
        • Saghazadeh Amene
        • Rezaei Nima
        Anti-inflammatory and M2 macrophage polarization-promoting effect of mesenchymal stem cell-derived exosomes.
        Int Immunopharmacol. 2021; 97107823https://doi.org/10.1016/j.intimp.2021.107823
        • Maacha Selma
        • Sidahmed Heba
        • Jacob Shana
        • Gentilcore Giusy
        • Calzone Rita
        • Grivel Jean-Charles
        • et al.
        Paracrine Mechanisms of Mesenchymal Stromal Cells in Angiogenesis.
        Stem Cells Int. 2020; 20204356359https://doi.org/10.1155/2020/4356359
        • Chang Calvin
        • Yan Jerry
        • Yao Zhicheng
        • Zhang Chi
        • Li Xiaowei
        • Mao Hai-Quan
        Effects of mesenchymal stem cell-derived paracrine signals and their delivery strategies.
        Adv Healthc Mater. 2021; 10e2001689https://doi.org/10.1002/adhm.202001689
        • Nolta Jan A
        Mechanisms of modulation and differentiation in mesenchymal stem/stromal cells.
        Stem Cells. 2021; 39: 1-2https://doi.org/10.1002/stem.3321
        • Eliopoulos Nicoletta
        • Zhao Jing
        • Bouchentouf Manaf
        • Forner Kathy
        • Birman Elena
        • Yuan Shala
        • et al.
        Human marrow-derived mesenchymal stromal cells decrease cisplatin renotoxicity in vitro and in vivo and enhance survival of mice post-intraperitoneal injection.
        Am J Physiol Renal Physiol. 2010; 299: F1288-F1298https://doi.org/10.1152/ajprenal.00671.2009
        • Mao Chenggang
        • Hou Xu
        • Wang Benzhen
        • Chi Jingwei
        • Jiang Yanjie
        • Zhang Caining
        • et al.
        Intramuscular injection of human umbilical cord-derived mesenchymal stem cells improves cardiac function in dilated cardiomyopathy rats.
        Stem Cell Res Ther. 2017; 8: 18https://doi.org/10.1186/s13287-017-0472-y
        • Yan Jianxin
        • Liang Jiaji
        • Cao Yingxuan
        • El Akkawi Mariya M
        • Liao Xuan
        • Chen Xiaojia
        • et al.
        Efficacy of topical and systemic transplantation of mesenchymal stem cells in a rat model of diabetic ischemic wounds.
        Stem Cell Res Ther. 2021; 12: 220https://doi.org/10.1186/s13287-021-02288-8
        • Tong Chuan
        • Hao Haojie
        • Xia Lei
        • Liu Jiejie
        • Ti Dongdong
        • Dong Liang
        • et al.
        Hypoxia pretreatment of bone marrow-derived mesenchymal stem cells seeded in a collagen-chitosan sponge scaffold promotes skin wound healing in diabetic rats with hindlimb ischemia.
        Wound Repair Regen. 2016; 24: 45-56https://doi.org/10.1111/wrr.12369
        • An Tao
        • Chen Yi
        • Tu Yingchun
        • Lin Ping
        Mesenchymal stromal cell-derived extracellular vesicles in the treatment of diabetic foot ulcers: application and challenges.
        Stem Cell Rev Rep. 2021; 17: 369-378https://doi.org/10.1007/s12015-020-10014-9
        • Trinh Nhu-Thuy
        • Yamashita Toshiharu
        • Ohneda Kinuko
        • Kimura Kenichi
        • To'a Salazar Georgina
        • Sato Fujio
        • et al.
        Increased expression of EGR-1 in diabetic human adipose tissue-derived mesenchymal stem cells reduces their wound healing capacity.
        Stem Cells Dev. 2016; 25: 760-773https://doi.org/10.1089/scd.2015.0335
        • Mendez Julio J
        • Ghaedi Mahboobe
        • Sivarapatna Amogh
        • Dimitrievska Sashka
        • Shao Zhen
        • Osuji Chinedum O
        • et al.
        Mesenchymal stromal cells form vascular tubes when placed in fibrin sealant and accelerate wound healing in vivo.
        Biomaterials. 2015; 40: 61-71https://doi.org/10.1016/j.biomaterials.2014.11.011
        • Cunha Carla
        • Pereira Catarina Leite
        • Ferreira Joana R
        • Ribeiro-Machado Cláudia
        • Grad Sibylle
        • Santos Susana G
        • et al.
        Therapeutic strategies for IVD Regeneration through Hyaluronan/SDF-1-Based Hydrogel and Intravenous Administration of MSCs.
        Int J Mol Sci. 2021; 22: 9609https://doi.org/10.3390/ijms22179609
        • Hedhli Jamila
        • Konopka Christian J
        • Schuh Sarah
        • Bouvin Hannah
        • Cole John A
        • Huntsman Heather D
        • et al.
        Multimodal Assessment of Mesenchymal Stem Cell Therapy for Diabetic Vascular Complications.
        Theranostics. 2017; 7: 3876-3888https://doi.org/10.7150/thno.19547
        • Gu Chengwei
        • Huang Sha
        • Gao Dongyun
        • Wu Yan
        • Li Jiwei
        • Ma Kui
        • et al.
        Angiogenic effect of mesenchymal stem cells as a therapeutic target for enhancing diabetic wound healing.
        Int J Low Extrem Wounds. 2014; 13: 88-93https://doi.org/10.1177/1534734614534977
        • Kong Poren
        • Xie Xiaoyun
        • Li Fang
        • Liu Yang
        • Lu Yingli
        Placenta mesenchymal stem cell accelerates wound healing by enhancing angiogenesis in diabetic Goto-Kakizaki (GK) rats.
        Biochem Biophys Res Commun. 2013; 438: 410-419https://doi.org/10.1016/j.bbrc.2013.07.088
        • Kurte Mónica
        • Vega-Letter Ana María
        • Luz-Crawford Patricia
        • Djouad Farida
        • Noël Danièle
        • Khoury Maroun
        • et al.
        Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE.
        Stem Cell Res Ther. 2020; 11: 416https://doi.org/10.1186/s13287-020-01840-2
        • Bernardini Chiara
        • Bertocchi Martina
        • Zannoni Augusta
        • Salaroli Roberta
        • Tubon Irvin
        • Dothel Giovanni
        • et al.
        Constitutive and LPS-stimulated secretome of porcine Vascular Wall-Mesenchymal Stem Cells exerts effects on in vitro endothelial angiogenesis.
        BMC Vet Res. 2019; 15: 123https://doi.org/10.1186/s12917-019-1873-1
        • Saeedi Pardis
        • Halabian Raheleh
        • Fooladi Abbas Ali Imani
        Antimicrobial effects of mesenchymal stem cells primed by modified LPS on bacterial clearance in sepsis.
        J Cell Physiol. 2019; 234: 4970-4986https://doi.org/10.1002/jcp.27298
        • Philipp Denise
        • Suhr Laura
        • Wahlers Thorsten
        • Choi Yeong-Hoon
        • Paunel-Görgülü Adnana
        Preconditioning of bone marrow-derived mesenchymal stem cells highly strengthens their potential to promote IL-6-dependent M2b polarization.
        Stem Cell Res Ther. 2018; 9: 286https://doi.org/10.1186/s13287-018-1039-2
        • Yue Chun
        • Guo Zi
        • Luo Yufang
        • Yuan Jingjing
        Xinxing Wan, Zhaohui Mo. c-Jun overexpression accelerates wound healing in diabetic rats by human umbilical cord-derived mesenchymal stem cells.
        Stem Cells Int. 2020; 20207430968https://doi.org/10.1155/2020/7430968
        • Mostafavinia Ataroalsadat
        • Amini Abdodlah
        • Ghorishi Seyed Kamran
        • Pouriran Ramin
        • Bayat Mohammad
        The effects of dosage and the routes of administrations of streptozotocin and alloxan on induction rate of type1 diabetes mellitus and mortality rate in rats.
        Lab Anim Res. 2016; 32: 160-165https://doi.org/10.5625/lar.2016.32.3.160
        • Achour M.
        • Jacq X.
        • Rondé P.
        • Alhosin M.
        • Charlot C.
        • Chataigneau T.
        • et al.
        The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression.
        Oncogene. 2008; 27: 2187-2197https://doi.org/10.1038/sj.onc.1210855
        • Ti Dongdong
        • Hao Haojie
        • Tong Chuan
        • Liu Jiejie
        • Dong Liang
        • Zheng Jingxi
        • et al.
        LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b.
        J Transl Med. 2015; 13: 308https://doi.org/10.1186/s12967-015-0642-6
        • Rodríguez-Vera D.
        • Abad-García A.
        • Vargas-Mendoza N.
        • Pinto-Almazán Rodolfo
        • Farfán-García Eunice D
        • Morales-González José A
        • et al.
        Polyphenols as potential enhancers of stem cell therapy against neurodegeneration.
        Neural Regen Res. 2022; 17: 2093-2101https://doi.org/10.4103/1673-5374.335826
        • Sun Chuang
        • Zhang Ao-Dan
        • Chen Hong-Hai
        • Bian Jie
        • Liu Zheng-Juan
        Magnet-targeted delivery of bone marrow-derived mesenchymal stem cells improves therapeutic efficacy following hypoxic-ischemic brain injury.
        Neural Regen Res. 2021; 16: 2324-2329https://doi.org/10.4103/1673-5374.310942
        • Li Xiang-Jun
        • Li Chun-Yan
        • Bai Dan
        • Leng Ying
        Insights into stem cell therapy for diabetic retinopathy: a bibliometric and visual analysis.
        Neural Regen Res. 2021; 16: 172-178https://doi.org/10.4103/1673-5374.286974
        • Chen Mei-Ting
        • Zhao Yi-Ting
        • Zhou Li-Yuan
        • Li Ming
        • Zhang Qian
        • Han Qin
        • et al.
        Exosomes derived from human umbilical cord mesenchymal stem cells enhance insulin sensitivity in insulin resistant human adipocytes.
        Curr Med Sci. 2021; 41: 87-93https://doi.org/10.1007/s11596-021-2323-4
        • Huang Qing
        • Ding Yi
        • Yu Ji-Guo
        • Li Jing
        • Xiang Yi
        • Tao Na
        Induction of differentiation of mesenchymal stem cells into retinal pigment epithelial cells for retinal regeneration by using ciliary neurotrophic factor in diabetic rats.
        Curr Med Sci. 2021; 41: 145-152https://doi.org/10.1007/s11596-021-2329-y
        • Wang Linhao
        • Wang Fang
        • Zhao Liling
        • Yang Wenjun
        • Wan Xinxing
        • al Chun
        Mesenchymal stem cells coated by the extracellular matrix promote wound healing in diabetic rats.
        Stem Cells Int. 2019; 20199564869https://doi.org/10.1155/2019/9564869
        • Huang Yi-Zhou
        • Gou Min
        • Da Lin-Cui
        • Zhang Wen-Qian
        • Xie Hui-Qi
        Mesenchymal stem cells for chronic wound healing: current status of preclinical and clinical studies.
        Tissue Eng Part B Rev. 2020; 26: 555-570https://doi.org/10.1089/ten.TEB.2019.0351
        • Jiang Dongsheng
        • Singh Karmveer
        • Muschhammer Jana
        • Schatz Susanne
        • Sindrilaru Anca
        • Makrantonaki Evgenia
        • et al.
        MSCs rescue impaired wound healing in a murine LAD1 model by adaptive responses to low TGF-β1 levels.
        EMBO Rep. 2020; 21: e49115https://doi.org/10.15252/embr.201949115
        • Yang Rong-Hua
        • Qi Shao-Hai
        • Shu Bin
        • Ruan Shu-Bin
        • Lin Ze-Peng
        • Lin Yan
        • et al.
        Epidermal stem cells (ESCs) accelerate diabetic wound healing via the Notch signalling pathway.
        Biosci. Rep. 2016; 36: e00364https://doi.org/10.1042/BSR20160034
        • Zhang Qi
        • Wan Xin-Xing
        • Hu Xi-Min
        • Zhao Wen-Juan
        • Ban Xiao-Xia
        • Huang Yan-Xia
        • et al.
        Targeting programmed cell death to improve stem cell therapy: implications for treating diabetes and diabetes-related diseases.
        Front Cell Dev Biol. 2021; 9809656https://doi.org/10.3389/fcell.2021.809656
        • Kim Soo
        • Park Joonghoon
        • Kim Tae Min
        Mesenchymal stem cell-derived extracellular vesicles for skin wound healing.
        Adv Exp Med Biol. 2021; 1310: 495-507https://doi.org/10.1007/978-981-33-6064-8_18
        • Lee Dylan E
        • Ayoub Nagi
        • Agrawal Devendra K
        Mesenchymal stem cells and cutaneous wound healing: novel methods to increase cell delivery and therapeutic efficacy.
        Stem Cell Res Ther. 2016; 7: 37https://doi.org/10.1186/s13287-016-0303-6
        • Motegi Sei-Ichiro
        • Ishikawa Osamu
        Mesenchymal stem cells: the roles and functions in cutaneous wound healing and tumor growth.
        J Dermatol Sci. 2017; 86: 83-89https://doi.org/10.1016/j.jdermsci.2016.11.005
        • Zhu Mengting
        • Chu Yunpeng
        • Shang Qianwen
        • Zheng Zhiyuan
        • Li Yanan
        • Cao Lijuan
        • et al.
        Mesenchymal stromal cells pretreated with pro-inflammatory cytokines promote skin wound healing through VEGFC-mediated angiogenesis.
        Stem Cells Transl Med. 2020; 9: 1218-1232https://doi.org/10.1002/sctm.19-0241
        • Ahmadi Houssein
        • Amini Abdollah
        • Fadaei Fathabady Fatemeh
        • Mostafavinia Atarodsadat
        • Zare Fatemeh
        • Ebrahimpour-Malekshah Roohollah
        • et al.
        Transplantation of photobiomodulation-preconditioned diabetic stem cells accelerates ischemic wound healing in diabetic rats.
        Stem Cell Res Ther. 2020; 11: 494https://doi.org/10.1186/s13287-020-01967-2
        • Yang Ronghua
        • Liu Fengxia
        • Wang Jingru
        • Chen Xiaodong
        • Xie Julin
        • Xiong Kun
        • et al.
        Epidermal stem cells in wound healing and their clinical applications.
        Stem Cell Res Ther. 2019; 10: 229https://doi.org/10.1186/s13287-019-1312-z
        • Kucharzewski Marek
        • Rojczyk Ewa
        • Wilemska-Kucharzewska Katarzyna
        • Wilk Renata
        • Hudecki Jacek
        • Los Marek J
        • et al.
        Novel trends in application of stem cells in skin wound healing.
        Eur J Pharmacol. 2019; 843: 307-315https://doi.org/10.1016/j.ejphar.2018.12.012
        • Tamari Masayuki
        • Nishino Yudai
        • Yamamoto Noriyuki
        • Ueda Minoru
        Acceleration of wound healing with stem cell-derived growth factors.
        Int J Oral Maxillofac Implants. 2013; 28: e369-e375https://doi.org/10.11607/jomi.te17
        • An Y.
        • Liu W.J.
        • Xue P.
        • Ma Y.
        • Zhang L.Q.
        • Zhu B.
        • et al.
        Autophagy promotes MSC-mediated vascularization in cutaneous wound healing via regulation of VEGF secretion.
        Cell Death Dis. 2018; 9: 58https://doi.org/10.1038/s41419-017-0082-8
        • Broekman Winifred
        • Amatngalim Gimano D
        • Mooij-Eijk Yvonne de
        • Oostendorp Jaap
        • Roelofs Helene
        • Taube Christian
        • et al.
        TNF-α and IL-1β-activated human mesenchymal stromal cells increase airway epithelial wound healing in vitro via activation of the epidermal growth factor receptor.
        Respir Res. 2016; 17: 3https://doi.org/10.1186/s12931-015-0316-1
        • Keul Jeon Young
        • Jang Yun Ho
        • Yoo Dong Ryeol
        • Kim Si Na
        • Lee Sang Koo
        • Nam Myeong Jin
        Mesenchymal stem cells' interaction with skin: wound-healing effect on fibroblast cells and skin tissue.
        Wound Repair Regen. 2010; 18: 655-661https://doi.org/10.1111/j.1524-475X.2010.00636.x
        • Jung Jae-A
        • Yoon Young-Don
        • Lee Hyup-Woo
        • Kang So-Ra
        • Han Seung-Kyu
        Comparison of human umbilical cord blood-derived mesenchymal stem cells with healthy fibroblasts on wound-healing activity of diabetic fibroblasts.
        Int Wound J. 2018; 15: 133-139https://doi.org/10.1111/iwj.12849
        • Huo Jiahui
        • Sun Sujing
        • Geng Zhijun
        • Sheng Wei
        • Chen Runkai
        • Ma Kui
        • et al.
        Bone Marrow-Derived Mesenchymal Stem Cells Promoted Cutaneous Wound Healing by Regulating Keratinocyte Migration via β 2-Adrenergic Receptor Signaling.
        Mol Pharm. 2018; 15: 2513-2527https://doi.org/10.1021/acs.molpharmaceut.7b01138
        • Maxson Scott
        • Lopez Erasmo A
        • Yoo Dana
        • Danilkovitch-Miagkova Alla
        • Leroux Michelle A
        Concise review: role of mesenchymal stem cells in wound repair.
        Stem Cells Transl Med. 2012; 1: 142-149https://doi.org/10.5966/sctm.2011-0018
        • Shen Lei
        • Zeng Wen
        • Wu Yang-Xiao
        • Hou Chun-Li
        • Chen Wen
        • Yang Ming-Can
        • et al.
        Neurotrophin-3 accelerates wound healing in diabetic mice by promoting a paracrine response in mesenchymal stem cells.
        Cell Transplant. 2013; 22: 1011-1021https://doi.org/10.3727/096368912x657495
        • Moon Kyung-Chul
        • Lee Jong-Seok
        • Han Seung-Kyu
        • Lee Hyup-Woo
        • Dhong Eun-Sang
        Effects of human umbilical cord blood-derived mesenchymal stromal cells and dermal fibroblasts on diabetic wound healing.
        Cytotherapy. 2017; 19: 821-828https://doi.org/10.1016/j.jcyt.2017.03.074
        • Yang Ronghua
        • Yang Shuai
        • Zhao Jingling
        • Hu Ximin
        • Chen Xiaodong
        • Wang Jingru
        • et al.
        Progress in studies of epidermal stem cells and their application in skin tissue engineering.
        Stem Cell Res Ther. 2020; 11: 303https://doi.org/10.1186/s13287-020-01796-3
        • Di Guohu
        • Du Xianli
        • Qi Xia
        • Zhao Xiaowen
        • Duan Haoyun
        • Li Suxia
        • et al.
        Mesenchymal Stem Cells Promote Diabetic Corneal Epithelial Wound Healing Through TSG-6-Dependent Stem Cell Activation and Macrophage Switch.
        Invest Ophthalmol Vis Sci. 2017; 58: 4344-4354https://doi.org/10.1167/iovs.17-21506
        • Huang Sha
        • Wu Yan
        • Gao Dongyun
        • Fu Xiaobing
        Paracrine action of mesenchymal stromal cells delivered by microspheres contributes to cutaneous wound healing and prevents scar formation in mice.
        Cytotherapy. 2015; 17: 922-931https://doi.org/10.1016/j.jcyt.2015.03.690
        • Yang Ronghua
        • Liu Fengxia
        • Wang Jingru
        • Chen Xiaodong
        • Xie Julin
        • Xiong Kun
        Epidermal stem cells in wound healing and their clinical applications.
        Stem Cell Res Ther. 2019; 10: 229https://doi.org/10.1186/s13287-019-1312-z
        • Hu X.M.
        • Li Z.X.
        • Zhang D.Y.
        • Yang Y.C.
        • Fu S.O.
        • Zhang Z.Q.
        • et al.
        A systematic summary of survival and death signalling during the life of hair follicle stem cells.
        Stem Cell Res Ther. 2021; 12: 453https://doi.org/10.1186/s13287-021-02527-y
        • Wang Z.L.
        • He R.Z.
        • Tu B.
        • He J.S.
        • Cao X.
        • Xia H.S.
        • et al.
        Drilling combined with adipose-derived stem cells and bone morphogenetic protein-2 to treat femoral head epiphyseal necrosis in juvenile rabbits.
        Current Medical Science. 2018; 38: 277-288https://doi.org/10.1007/s11596-018-1876-3
        • Ma Dongrui
        • Hsiang Kua Jonah Ee
        Wee Keng Lim, Seng Teik Lee, Alvin Wen Choong Chua. In vitro characterization of human hair follicle dermal sheath mesenchymal stromal cells and their potential in enhancing diabetic wound healing.
        Cytotherapy. 2015; 17: 1036-1051https://doi.org/10.1016/j.jcyt.2015.04.001
        • Maharlooei Mohsen Khosravi
        • Bagheri Mansooreh
        • Solhjou Zhabiz
        • Jahromi Behnam Moein
        • Akrami Majid
        • Rohani Lili
        • et al.
        Adipose tissue derived mesenchymal stem cell (AD-MSC) promotes skin wound healing in diabetic rats.
        Diabetes Res Clin Pract. 2011; 93: 228-234https://doi.org/10.1016/j.diabres.2011.04.018
        • Ma Kun
        • Liao Susan
        • He Liumin
        • Lu Jia
        • Ramakrishna Seeram
        • Chan Casey K
        Effects of nanofiber/stem cell composite on wound healing in acute full-thickness skin wounds.
        Tissue Eng Part A. 2011; 17: 1413-1424https://doi.org/10.1089/ten.TEA.2010.0373
        • Fu Xiaobing
        • Fang Lijun
        • Li Xiaokun
        • Cheng Biao
        • Sheng Zhiyong
        Enhanced wound-healing quality with bone marrow mesenchymal stem cells autografting after skin injury.
        Wound Repair Regen. 2006; 14: 325-335https://doi.org/10.1111/j.1743-6109.2006.00128.x
        • Yi Hanxiao
        • Wang Yang
        • Yang Zhen
        • Xie Zhiqin
        Efficacy assessment of mesenchymal stem cell transplantation for burn wounds in animals: a systematic review.
        Stem Cell Res Ther. 2020; 11: 372https://doi.org/10.1186/s13287-020-01879-1
        • Dash Surjya Narayan
        • Dash Nihar Ranjan
        • Guru Bhikaricharan
        Prakash Chandra Mohapatra. Towards reaching the target: clinical application of mesenchymal stem cells for diabetic foot ulcers.
        Rejuvenation Res. 2014; 17: 40-53https://doi.org/10.1089/rej.2013.1467
        • Laloze Jérôme
        • Fiévet Loïc
        • Desmoulière Alexis
        Adipose-Derived Mesenchymal Stromal Cells in Regenerative Medicine: state of Play, Current Clinical Trials, and Future Prospects.
        Adv Wound Care (New Rochelle). 2021; 10: 24-48https://doi.org/10.1089/wound.2020.1175
        • Li Zhonghua
        • Wang Haiqin
        • Yang Bo
        • Sun Yukai
        • Huo Ran
        Three-dimensional graphene foams loaded with bone marrow derived mesenchymal stem cells promote skin wound healing with reduced scarring.
        Mater Sci Eng C Mater Biol Appl. 2015; 57: 181-188https://doi.org/10.1016/j.msec.2015.07.062
        • Li Haihong
        • Fu Xiaobing
        Mechanisms of action of mesenchymal stem cells in cutaneous wound repair and regeneration.
        Cell Tissue Res. 2012; 348: 371-377https://doi.org/10.1007/s00441-012-1393-9
        • Lee Sei-Jung
        • Jung Young Hyun
        • Oh Sang Yub
        • Yun Seung Pil
        • Han Ho Jae
        Melatonin enhances the human mesenchymal stem cells motility via melatonin receptor 2 coupling with Gαq in skin wound healing.
        J Pineal Res. 2014; 57: 393-407https://doi.org/10.1111/jpi.12179
        • Tang J.
        • Wu T.
        • Xiong J.
        • Su Y.
        • Zhang C.
        • Wang S.
        • et al.
        Porphyromonas gingivalis lipopolysaccharides regulate functions of bone marrow mesenchymal stem cells.
        Cell Prolif. 2015; 48: 239-248https://doi.org/10.1111/cpr.12173
        • Fiedler Tomas
        • Salamon Achim
        • Adam Stefanie
        • Herzmann Nicole
        • Taubenheim Jan
        • Peters Kirsten
        Impact of bacteria and bacterial components on osteogenic and adipogenic differentiation of adipose-derived mesenchymal stem cells.
        Exp Cell Res. 2013; 319: 2883-2892https://doi.org/10.1016/j.yexcr.2013.08.020
        • Fu Xiaobing
        • Li Haihong
        Mesenchymal stem cells and skin wound repair and regeneration: possibilities and questions.
        Cell Tissue Res. 2009; 335: 317-321https://doi.org/10.1007/s00441-008-0724-3
        • Zomer Helena Debiazi
        • Varela Gisele Kristina Dos Santos
        • Delben Priscilla Barros
        • Heck Diana
        Talita da Silva Jeremias, Andrea Gonçalves Trentin. In vitro comparative study of human mesenchymal stromal cells from dermis and adipose tissue for application in skin wound healing.
        J Tissue Eng Regen Med. 2019; 13: 729-741https://doi.org/10.1002/term.2820
        • Chen Enlin
        • Chen Zhe
        • Chen Linxi
        • Hu Xiaoling
        Platelet-derived respiratory-competent mitochondria transfer to mesenchymal stem cells to promote wound healing via metabolic reprogramming.
        Platelets. 2022; 33: 171-173https://doi.org/10.1080/09537104.2021.1961717
        • Sharma Preety
        • Kumar Arun
        • Deka Dey Asmita
        • Behl Tapan
        • Chadha Swati
        Stem cells and growth factors-based delivery approaches for chronic wound repair and regeneration: a promise to heal from within.
        Life Sci. 2021; 268118932https://doi.org/10.1016/j.lfs.2020.118932
        • Qi Kai
        • Li Na
        • Zhang Zhenyu
        • Melino Gerry
        Tissue regeneration: the crosstalk between mesenchymal stem cells and immune response.
        Cell Immunol. 2018; 326: 86-93https://doi.org/10.1016/j.cellimm.2017.11.010
        • Khalid Ramla Sana
        • Khan Irfan
        • Zaidi Midhat Batool
        • Naeem Nadia
        • Haneef Kanwal
        • Qazi Rida-E-Maria
        • et al.
        IL-7 overexpression enhances therapeutic potential of rat bone marrow mesenchymal stem cells for diabetic wounds.
        Cell Immunol. 2018; 326: 86-93https://doi.org/10.1111/wrr.12706
        • Li Haihong
        • Fu Xiaobing
        • Ouyang Yunshu
        • Cai Cunliang
        • Wang Jun
        • Sun Tongzhu
        Adult bone-marrow-derived mesenchymal stem cells contribute to wound healing of skin appendages.
        Cell Tissue Res. 2006; 326: 725-736https://doi.org/10.1007/s00441-006-0270-9
        • Landry Yannick
        • Lê Oanh
        • Mace Kimberly A
        • Restivo Terry E
        • Beauséjour Christian M
        Secretion of SDF-1alpha by bone marrow-derived stromal cells enhances skin wound healing of C57BL/6 mice exposed to ionizing radiation.
        J Cell Mol Med. 2010; 14: 1594-1604https://doi.org/10.1111/j.1582-4934.2009.00887.x
        • Marusina Alina I
        • Merleev Alexander A
        • Luna Jesus I
        • Olney Laura
        • Haigh Nathan E
        • Yoon Daniel
        • et al.
        Tunable hydrogels for mesenchymal stem cell delivery: integrin-induced transcriptome alterations and hydrogel optimization for human wound healing.
        Stem Cells. 2020; 38: 231-245https://doi.org/10.1002/stem.3105
        • Maranda Eric L
        • Rodriguez-Menocal Luis
        • Badiavas Evangelos V
        Role of mesenchymal stem cells in dermal repair in burns and diabetic wounds.
        Curr Stem Cell Res Ther. 2017; 12: 61-70https://doi.org/10.2174/1574888x11666160714115926
        • Zhang Qun-Zhou
        • Su Wen-Ru
        • Shi Shi-Hong
        • Wilder-Smith Petra
        • Xiang Andy Peng
        • Wong Alex
        • et al.
        Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing.
        Stem Cells. 2010; 28: 1856-1868https://doi.org/10.1002/stem.503
        • Bist Deepika
        • Pawde A.M.
        • Amarpal Prakash Kinjavdekar
        • Mukherjee Reena
        • Singh K.P.
        • et al.
        Evaluation of canine bone marrow-derived mesenchymal stem cells for experimental full-thickness cutaneous wounds in a diabetic rat model.
        Expert Opin Biol Ther. 2021; 21: 1655-1664https://doi.org/10.1080/14712598.2022.1990260
        • Wan X.X.
        • Zhang D.Y.
        • Khan M.A.
        • Zheng S.Y.
        • Hu X.M.
        • Zhang Q.
        • et al.
        Stem cell transplantation in the treatment of type 1 diabetes mellitus: from insulin replacement to beta cells replacement.
        Front Endocrinol (Lausanne). 2022; 13859638https://doi.org/10.3389/fendo.2022.859638
        • Hu X.M.
        • Zhang Q.
        • Zhang R.X.
        • Wu Y.L.
        • Li Z.X.
        • Zhang D.Y.
        • et al.
        Programmed cell death in stem cell-based therapy: mechanisms and clinical applications.
        World J Stem Cells. 2021; 13: 386-415https://doi.org/10.4252/wjsc.v13.i5.386
        • Liang Xiaoting
        • Lin Fang
        • Ding Yue
        • Zhang Yuelin
        • Li Mimi
        • Zhou Xiaohui
        • et al.
        Conditioned medium from induced pluripotent stem cell-derived mesenchymal stem cells accelerates cutaneous wound healing through enhanced angiogenesis.
        Stem Cell Res Ther. 2021; 12: 295https://doi.org/10.1186/s13287-021-02366-x
        • Joseph Anand
        • Baiju Indu
        • Bhat Irfan A
        • Pandey Sriti
        • Bharti Mukesh
        • Verma Megha
        • et al.
        Mesenchymal stem cell-conditioned media: a novel alternative of stem cell therapy for quality wound healing.
        J Cell Physiol. 2020; 235: 5555-5569https://doi.org/10.1002/jcp.29486
        • Wu Yaojiong
        • Chen Liwen
        • Scott Paul G
        • Tredget Edward E
        Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis.
        Stem Cells. 2007; 25: 2648-2659https://doi.org/10.1634/stemcells.2007-0226
        • Li Yunling
        • Zheng Lei
        • Xu Xia
        • Song Lili
        • Li Yin
        • Li Wei
        • et al.
        Mesenchymal stem cells modified with angiopoietin-1 gene promote wound healing.
        Stem Cell Res Ther. 2013; 4: 113https://doi.org/10.1186/scrt324