Review Article| Volume 195, 110201, January 2023

Bone marrow-derived mesenchymal stem cells: A promising therapeutic option for the treatment of diabetic foot ulcers

  • Ganesh Dama
    Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China

    Department of Community Health, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Malaysia
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  • Jiang Du
    Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China

    College of Medical Engineering, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China
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  • Xinxing Zhu
    Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China

    College of Medical Engineering, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China
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  • Yanli Liu
    Corresponding authors at: No. 601, East of JinSui Road, Xinxiang City, Henan Province, China.
    Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China

    College of Life Sciences and Technology, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China
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  • Juntang Lin
    Corresponding authors at: No. 601, East of JinSui Road, Xinxiang City, Henan Province, China.
    Stem Cell and Biotherapy Engineering Research Center of Henan, Henan Joint International Research Laboratory of Stem Cell Medicine, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China

    College of Medical Engineering, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China

    College of Life Sciences and Technology, Xinxiang Medical University, East of JinSui Road #601, 453003 Xinxiang, China
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Published:December 06, 2022DOI:


      Chronic wounds fail to heal through the three normal stages of healing (inflammatory, proliferative, and remodelling), resulting in a chronic tissue injury that is not repaired within the average time limit. Patients suffering from type 1 and type 2 diabetes are prone to develop diabetic foot ulcers (DFUs), which commonly develop into chronic wounds that are non treatable with conventional therapies. DFU develops due to various risk factors, such as peripheral neuropathy, peripheral vascular disease, arterial insufficiency, foot deformities, trauma and impaired resistance to infection. DFUs have gradually become a major problem in the health care system worldwide. In this review, we not only focus on the pathogenesis of DFU but also comprehensively summarize the outcomes of preclinical and clinical studies thus far and the potential therapeutic mechanism of bone marrow-derived mesenchymal stem cells (BMSCs) for the treatment of DFU. Based on the published results, BMSC transplantation can contribute to wound healing through growth factor secretion, anti-inflammation, differentiation into tissue-specific cells, neovascularization, re-epithelialization and angiogenesis in DFUs. Moreover, clinical trials showed that BMSC treatment in patients with diabetic ulcers improved ulcer healing and the ankle-brachial index, ameliorated pain scores, and enhanced claudication walking distances with no reported complications. In conclusion, although BMSC transplantation exhibits promising therapeutic potential in DFU treatment, additional studies should be performed to confirm their efficacy and long-term safety in DFU patients.



      DFU (Diabetic foot ulcer), BMSCs (Bone marrow-derived mesenchymal stem cells), PN (Peripheral neuropathy), PVD (Peripheral vascular disease), MSCs (Mesenchymal stem cells), IGF-1 (Insulin like growth factor 1), KGF (Keratinocyte growth factor), EGF (Epidermal growth factor), SDF-1 (stromal cell-derived factor1), EPO (Erythropoietin), PECAM-1 (Platelet endothelial cell adhesion molecule-1), NGF (Nerve growth factor), PDGF (Platelet-derived growth factor BB), HGF (Hepatocyte growth factor), BDNF (Brain-derived neurotropic factor), bFGF (Basic fibroblast growth factor), ANG-2 (Plasma angiopoietin-2), VCAM1 (Vascular adhesion molecule 1-), ICAM1 (Intercellular adhesion molecule 1-), BMSC-CM (Bone marrow derived mesenchymal stem cells derived conditioned medium), C–C (chemokine receptor type 7 (CCR7)), CXCR4 (C-X-C Motif Chemokine Receptor 4), TSG-6 (Tumor necrosis factor- (TNF) stimulated gene-6)
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      1. Diabetes atlas. 6th ed. International Diabetes Federation 2013.

        • Whiting D.R.
        • Guariguata L.
        • Weil C.
        • Shaw J.
        IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030.
        Diabetes Res Clin Pract. 2011; 94: 311
      2. International Diabetes Federation. The global burden. IDF diabetes atlas. 5th. ed. 2012.

        • Grunfeld C.
        Diabetic foot ulcers: etiology, treatment and prevention.
        Adv Intern Med. 1992; 37: 103-132
        • Alvin C.
        Diabetes mellitus.
        in: Harrison T. Principle of internal medicine. 16th ed. McGraw-Hill Companies, New York2005: 830-835
        • Rathur H.M.
        • Boulton H.J.
        The diabetic foot.
        Clin Dermatol. 2007; 25: 109
      3. Boulton AJM, Whitehouse RW. The Diabetic Foot. In Endotext; Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, Dungan K, Grossman A, Hershman JM, Hofland J et al, Eds.;, Inc.: South Dartmouth, MA, USA, 2000.

        • Boyko E.J.
        • Ahroni J.H.
        • Smith D.G.
        • Davignon D.
        Increased mortality associated with diabetic foot ulcer.
        Diabet Med. 1996; 13: 967
        • Caravaggi C.
        • Ferraresi R.
        • Bassetti M.
        • Sganzaroli A.B.
        • Galenda P.
        • Fattori S.
        • et al.
        Management of ischemic diabetic foot.
        J Cardiovasc Surg (Torino). 2013; 54: 737-754
        • Ramsey S.D.
        • Newton K.
        • Blough D.
        • McCulloch D.K.
        • Sandhu N.
        • Reiber G.E.
        • et al.
        Incidence, outcomes and costs of foot ulcers in patients with diabetes.
        Diabetes Care. 1999; 22: 382-437
        • Krentz A.J.
        • Acheson P.
        • Basu A.
        • Kilvert A.
        • Wright A.D.
        • Natrass M.
        Morbidity and mortality associated with diabetic foot disease: a 12-month prospective survey of hospital admissions in a single UK centre.
        Foot. 1997; 7
        • Reed J.F.
        An audit of lower extremity complications in octogenarian patients with diabetes mellitus.
        Int J Low Extrem Wounds. 2004; 3: 161
        • Cao Y.
        • Gang X.
        • Sun C.
        • Wang G.
        Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer.
        J Diabetes Res. 2017; 2017: 9328347
        • Wu Y.
        • Chen L.
        • Scott P.G.
        • Tredget E.E.
        Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis.
        Stem Cells. 2007; 25: 2648
        • Vojtassák J.
        • Danisovic L.
        • Kubes M.
        • Bakos D.
        • Jarábek L.
        • Ulicná M.
        • et al.
        Autologous biograft and mesenchymal stem cells in treatment of the diabetic foot.
        Neuro Endocrinol Lett. 2006; 27: 134-217
        • Jiang X.Y.
        • Lu D.B.
        • Chen B.
        Progress in stem cell therapy for the diabetic foot.
        Diabetes Res Clin Pract. 2012; 97: 43
        • Li H.
        • Fu X.
        Mechanisms of action of mesenchymal stem cells in cutaneous wound repair and regeneration.
        Cell Tissue Res. 2012; 348
        • Amann B.
        • Luedemann C.
        • Ratei R.
        • Schmidt-Lucke J.A.
        Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease.
        Cell Transplant. 2009; 18: 371
        • Procházka V.
        • Gumulec J.
        • Chmelová J.
        • Klement P.
        • Klement G.L.
        • Jonszta T.
        • et al.
        Autologous bone marrow stem cell transplantation in patients with end-stage chronical critical limb ischemia and diabetic foot.
        Vnitr Lek. 2009; 55: 173-218
        • Boulton A.J.
        • Vileikytel L.
        • Ragnarson- Tennval G.
        • Apelqvist J.
        The global burden of diabetic foot disease.
        Lancet. 2005; 366
        • Khanolkar M.P.
        • Bain S.C.
        • Stephens J.W.
        The diabetic foot.
        QJM. 2008; 101: 685
        • Shaw J.E.
        • Boulton A.J.
        The pathogenesis of diabetic foot problems. An overview.
        Diabetes. 1997; 46: S58
        • Zubair M.
        • Malik A.
        • Ahmad J.
        Clinico-microbial study and anti-microbial drug resistance profile of diabetic foot infections in North India.
        Foot. 2011; 21: 6
        • Zochodone D.W.
        Diabetic polyneuropathy: an update.
        Curr Opin Neurol. 2008; 21: 527
        • Cameron N.E.
        • Cotter M.A.
        Comparison of the effects of ascorbylm- linolenic acid and m-linolenic acid in the correction of neurovascular deficits in diabetic rats.
        Diabetologia. 1996; 39: 1047
        • Xia P.
        • Inoguchi T.
        • Kern T.S.
        • Engerman R.L.
        • Oates P.J.
        • King G.L.
        Characterization of the mechanisms for the chronic activation of diacylglycerol-protein kinase C pathways in diabetes and hypergalactosemia.
        Diabetes. 1994; 43: 1122-2119
      4. Honing ML, Morrison PJ, Banga JD, Stroes ES, Rabelink TJ. Nitric oxide availability in diabetes mellitus. Diabetes Metab Rev. 1998; 14:241–19.<241::aid dmr216>;2-r.

        • Pittenger G.
        • Vinik A.
        Nerve growth factor and diabetic neuropathy.
        Exp Diabesity Res. 2003; 4: 271
        • Canal N.
        • Nemni R.
        Autoimmunity and diabetic neuropathy.
        Clin Neurosci. 1997; 4: 371-383
        • Brownlee M.
        The pathobiology of diabetic complications: a unifying mechanism.
        Diabetes. 2005; 54: 1615-1625
        • Steed D.L.
        Diabetic wounds, assessment, classification, and management.
        in: Krasner D. Rodeheaver G. Sibbald R.G. Chronic wound care: a clinical source book for healthcare professionals. Health Management Publications, Wayne, PA2001: 575-581
        • Gardner S.E.
        • Frantz R.A.
        Wound bioburden and infection-related complications in diabetic foot ulcers.
        Biol Res Nurs. 2008; 10: 44
        • Clayton W.
        • Elasy T.A.
        A review of pathophysiology, classification and treatment of foot ulcers in diabetic patients. Clin.
        Diabetes. 2009; 27: 52
        • Firnhaber J.M.
        • Powell C.S.
        Lower Extremity Peripheral Artery Disease: Diagnosis and Treatment.
        Am Fam Physician. 2019; 99: 362-439
        • Mohler 3rd., E.R.
        Therapy insight : peripheral arterial disease and diabetes : from pathogenesis to treatment guidelines.
        Nat Clin Pract Cardiovasc Med. 2007; 4
        • Williams D.T.
        • Hilton J.R.
        • Harding K.G.
        Diagnosing foot infection in diabetes.
        Clin Infect Dis. 2004; 39: 83
        • Candel Gonzalez F.J.
        • Alramadan M.
        • Metasanz M.
        • Diaz A.
        • Gonzalez Romo F.
        • Candel I.
        • et al.
        Infections of diabetic foot ulcer. Eur.
        Intern Med. 2003; 14: 341
        • Gardner S.E.
        • Hillis S.L.
        • Heilmann K.
        • Segre J.A.
        • Grice E.A.
        The neuropathic diabetic foot ulcer microbiome is associated with clinical factors.
        Diabetes. 2013; 62
        • Lipsky B.A.
        • Pecoraro R.E.
        • Wheat L.J.
        The diabetic foot: soft tissue and bone infection.
        Infect Dis Clin N Am. 1990; 4: 409-432
        • Dang C.N.
        • Prasad Y.D.
        • Boulton A.J.
        • Jude E.B.
        Methicillin resistant Staphylococcus aureus in the diabetic foot clinic: a worsening problem.
        Diabet Med. 2003; 20: 159
        • Hunt J.A.
        Foot infections in diabetes are rarely due to a single microorganism.
        Diabet Med. 1992; 9: 749
        • Caputo G.M.
        • Joshi N.
        • Weitekamp M.R.
        Foot infections in patients with diabetes.
        Am Fam Physician. 1997; 56
        • Frykberg R.G.
        An evidence based approach to diabetic foot infection.
        Am J Surg. 2003; 186
        • Dinh T.L.
        • Veves A.
        A review of the mechanisms implicated in the pathogenesis of the diabetic foot.
        Int J Low Extrem Wounds. 2005; 4: 154
        • Aleem M.A.
        Factors that precipitate development of diabetic foot ulcers in rural India.
        Lancet. 2003; 362: 1858
      5. Murray HJ, Young MJ, Boulton AJ. The relationship between callus formation, high pressures and neuropathy in diabetic foot ulceration. Diabet Med. 1996; 13:979–82.<979::AID-DIA267>3.0.CO;2-A.

        • Watkins P.J.
        The diabetic foot.
        BMJ. 2003; 326: 977-999
        • Bakker K.
        • Apelqvist J.
        • Lipsky B.A.
        • Van Netten J.J.
        • Schaper N.C.
        The 2015 IWGDF guidance on the prevention and management of foot problems in diabetes.
        Int Wound J. 2016; 13: 1072
        • Doupis J.
        • Veves A.
        Classification, diagnosis, and treatment of diabetic foot ulcers.
        Wounds. 2008; 20: 117-126
        • Hinchliffe R.J.
        • Valk G.D.
        • Apelqvist J.
        • Armstrong D.G.
        • Bakker K.
        • Game F.L.
        • et al.
        Specific guidelines on wound and wound-bed management.
        Diabetes Metab Res Rev. 2008; 24: 188
        • Jeffcoate W.J.
        • Lipsky B.A.
        • Berendt A.R.
        • Cavanagh P.R.
        • Bus S.A.
        • Peters E.J.G.
        • et al.
        Unresolved issues in the management of ulcers of the foot in diabetes.
        Diabet Med. 2008; 25:1380–89.
        • Fukuchi Y.
        • Nakajima H.
        • Sugiyama D.
        • Hirose I.
        • Kitamura T.
        • Tsuji K.
        Human placenta-derived cells have mesenchymal stem/progenitor cell potential.
        Stem Cells. 2004; 22:649–58.
        • Ilancheran S.
        • Moodley Y.
        • Manuelpillai U.
        Human fetal membranes: a source of stem cells for tissue regeneration and repair?.
        Placenta. 2009; 30
        • Christodoulou I.
        • Goulielmaki M.
        • Devetzi M.
        • Panagiotidis M.
        • Koliakos G.
        • Zoumpourlis V.
        Mesenchymal stem cells in preclinical cancer cytotherapy: a systematic review.
        Stem Cell Res Ther. 2018; 9: 336
        • Wang S.
        • Miao Z.
        • Yang Q.
        • Wang Y.
        • Zhang J.
        The dynamic roles of mesenchymal stem cells in colon cancer. Can.
        J Gastroenterol Hepatol. 2018; 2018:7628763.
        • Yun C.W.
        • Lee S.H.
        Enhancement of functionality and therapeutic efficacy of cell-based therapy using mesenchymal stem cells for cardiovascular disease.
        Int J Mol Sci. 2019; 20
        • Ward M.R.
        • Abadeh A.
        • Connelly K.A.
        Concise review: rational use of mesenchymal stem cells in the treatment of ischemic heart disease.
        Stem Cells Transl Med. 2018; 7: 543-550
        • Monsel A.
        • Zhu Y.G.
        • Gennai S.
        • Hao Q.
        • Hu S.
        • Rouby J.J.
        • et al.
        Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice.
        Am J Respir Crit Care Med. 2015; 192
        • Mendonça L.
        • Felix N.S.
        • Blanco N.G.
        • Da Silva J.S.
        • Ferreira T.P.
        • Abreu S.C.
        • et al.
        Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension.
        Stem Cell Res Ther. 2017; 8: 220
        • Mosna F.
        • Sensebe L.
        • Krampera M.
        Human bone marrow and adipose tissue mesenchymal stem cells: a user's guide.
        Stem Cells Dev. 2010; 19:1449–70.
        • Vellasamy S.
        • Sandrasaigaran P.
        • Vidyadaran S.
        • George E.
        • Ramasamy R.
        Isolation and characterisation of mesenchymal stem cells derived from human placenta tissue. World.
        J Stem Cells. 2012; 4:53–61.
      6. Batsali AK, Kastrinaki MC, Papadaki HA, Pontikoglou C. Mesenchymal stem cells derived from Wharton's Jelly of the umbilical cord: biological properties and emerging clinical applications. Curr Stem Cell Res Ther. 2013; 8: 144–55.

        • Wu Y.
        • Wang J.
        • Scott P.G.
        • Tredget E.E.
        Bone marrow-derived stem cells in wound healing: a review.
        Wound Repair Regen. 2007; 15:18–26.
        • Fu X.
        • Li H.
        Mesenchymal stem cells and skin wound repair and regeneration: possibilities and questions.
        Cell Tissue Res. 2009; 335:317–21.
        • Fathke C.
        • Wilson L.
        • Hutter J.
        • Kapoor V.
        • Smith A.
        • Hocking A.
        • et al.
        Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair.
        Stem Cells. 2004; 22
        • Gillitzer R.
        • Goebeler M.
        Chemokines in cutaneous wound healing.
        J Leukoc Biol. 2001; 69: 513-521
        • Kolf C.M.
        • Cho E.
        • Tuan R.S.
        Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation.
        Arthritis Res Ther. 2007; 9:204.
        • Ishii G.
        • Sangai T.
        • Sugiyama K.
        • Ito T.
        • Hasebe T.
        • Endoh Y.
        • et al.
        In vivo characterization of bone marrow-derived fibroblasts recruited into fibrotic lesions.
        Stem Cells. 2005; 23:699–06.
        • Deng W.
        • Han Q.
        • Liao L.
        • Li C.
        • Ge W.
        • Zhao Z.
        • et al.
        Engrafted bone marrow-derived flk-(1) mesenchymal stem cells regenerate skin tissue.
        Tissue Eng. 2005;
        • Mori L.
        • Bellini A.
        • Stacey M.A.
        • Schmidt M.
        • Mattoli S.
        Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow.
        Exp Cell Res. 2005; 304:81–90.
        • Le Blanc K.
        Immunomodulatory effects of fetal and adult mesenchymal stem cells.
        Cytotherapy. 2003; 5: 485-549
        • Di Nicola M.
        • Carlo-Stella C.
        • Magni M.
        • Milanesi M.
        • Longoni P.D.
        • Matteucci P.
        • et al.
        Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli.
        Blood. 2002; 99:3838–43.
        • Krampera M.
        • Cosmi L.
        • Angeli R.
        • Pasini A.
        • Liotta F.
        • Andreini A.
        • et al.
        Role for interferon-γ in the immunomodulatory activity of human bone marrow mesenchymal stem cells.
        Stem Cells. 2006; 24: 386-398
        • Hua J.
        • Gong J.
        • Meng H.
        • Xu B.
        • Yao L.
        • Qian M.
        • et al.
        Comparison of different methods for the isolation of mesenchymal stem cells from umbilical cord matrix: proliferation and multilineage differentiation as compared to mesenchymal stem cells from umbilical cord blood and bone marrow.
        Cell Biol Int. 2014; 38:198–10.
        • Kwon D.S.
        • Gao X.
        • Liu Y.B.
        • Dulchavsky D.S.
        • Danyluk A.L.
        • Bansal M.
        • et al.
        Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats.
        Int Wound J. 2008; 5: 453-463
      7. Chen L, Tredget EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008; 3:e1886.

        • Wan J.
        • Xia L.
        • Liang W.
        • Liu Y.
        • Cai Q.
        Transplantation of bone marrow-derived mesenchymal stem cells promotes delayed wound healing in diabetic rats.
        J Diabetes Res. 2013; 2013:647107.
        • Inoue H.
        • Murakami T.
        • Ajiki T.
        • Hara M.
        • Hoshino Y.
        • Kobayashi E.
        Bioimaging assessment and effect of skin wound healing using bone-marrow-derived mesenchymal stromal cells with the artificial dermis in diabetic rats.
        J Biomed Opt. 2008; 13064036
        • O'Loughlin A.
        • Kulkarni M.
        • Creane M.
        • Vaughan E.E.
        • Mooney E.
        • Shaw G.
        • et al.
        Topical administration of allogeneic mesenchymal stromal cells seeded in a collagen scaffold augments wound healing and increases angiogenesis in the diabetic rabbit ulcer.
        Diabetes. 2013; 62: 2588-2594
        • Shen L.
        • Zeng W.
        • Wu Y.X.
        • Hou C.L.
        • Chen W.
        • Yang M.C.
        • et al.
        Neurotrophin-3 accelerates wound healing in diabetic mice by promoting a paracrine response in mesenchymal stem cells.
        Cell Transplant. 2013; 22:1011–21.
        • Hou C.
        • Shen L.
        • Huang Q.
        • Mi J.
        • Wu Y.
        • Yang M.
        • et al.
        The effect of heme oxygenase-1 complexed with collagen on MSC performance in the treatment of diabetic ischemic ulcer.
        Biomaterials. 2013; 34:112–20.
        • Amin A.H.
        • Abd Elmageed Z.Y.
        • Nair D.
        • Partyka M.I.
        • Kadowitz P.J.
        • Belmadani S.
        • et al.
        Modifed multipotent stromal cells with epidermal growth factor restore vasculogenesis and blood flow in ischemic hind-limb of type II diabetic mice.
        Lab Invest. 2010; 90:985–96.
        • Kato J.
        • Kamiya H.
        • Himeno T.
        • Shibata T.
        • Kondo M.
        • Okawa T.
        • et al.
        Mesenchymal stem cells ameliorate impaired wound healing through enhancing keratinocyte functions in diabetic foot ulcerations on the plantar skin of rats.
        J Diabetes Complications. 2014; 28: 588-595
        • Li M.
        • Zhao Y.
        • Hao H.
        • Dai H.
        • Han Q.
        • Tong C.
        • et al.
        Mesenchymal stem cell conditioned medium improves the proliferation and migration of keratinocytes in a diabetes-like microenvironment.
        Int J Low Extrem Wounds. 2015; 14: 73-86
        • Falanga V.
        • Iwamoto S.
        • Chartier M.
        • Yufit T.
        • Butmarc J.
        • Kouttab N.
        • et al.
        Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds.
        Tissue Eng. 2007; 13: 1299-11212
        • Assi R.
        • Foster T.R.
        • He H.
        • Stamati K.
        • Bai H.
        • Huang Y.
        • et al.
        Delivery of mesenchymal stem cells in biomimetic engineered scaffolds promotes healing of diabetic ulcers.
        Regen Med. 2016; 11: 245-260
      8. Lamiaa M, Shawky, Eman A, El Bana, Ahmed A, Morsi. Stem cells and metformin synergistically promote healing in experimentally induced cutaneous wound injury in diabetic rats. Folia Histochem Cytobiol. 2019; 57:127-38. 10.5603/FHC.a2019.0014.

        • Bai H.
        • Cheol N.K.
        • Wang Z.
        • Cui Y.
        • Liu H.
        • Feng Y.
        • et al.
        Regulation of inflammatory microenvironment using a self-healing hydrogel loaded with BM-MSCs for advanced wound healing in rat diabetic foot ulcers.
        J Tissue Eng. 2020; 31: 1-13
        • Lian Z.
        • Yin X.
        • Li H.
        • Jia L.
        • He X.
        • Yan Y.
        • et al.
        Synergistic effect of bone marrow-derived mesenchymal stem cells and platelet-rich plasma in streptozotocin-induced diabetic rats.
        Ann Dermatol. 2014; 26: 1-10
        • Amini A.
        • Pouriran R.
        • Abdollahifar M.A.
        • Abbaszadeh H.A.
        • Ghoreishi S.K.
        • Chien S.
        • et al.
        Stereological and molecular studies on the combined effects of photobiomodulation and human bone marrow mesenchymal stem cell conditioned medium on wound healing in diabetic rats.
        J Photochem Photobiol B. 2018; 182: 42-51
        • Bagheri M.
        • Amini A.
        • Abdollahifar M.A.
        • Ghoreishi S.K.
        • Piryaei A.
        • Pouriran R.
        • et al.
        Effects of Photobiomodulation on Degranulation and Number of Mast Cells and Wound Strength in Skin Wound Healing of Streptozotocin-Induced Diabetic Rats.
        Photomed Laser Surg. 2018; 36: 415-423
      9. Fridoni M , kouhkheil R, Abdollhifar MA, Amini A , Ghatrehsamani M , Ghoreishi SK , Chien S , Bayat S , Bayat M. Improvement in infected wound healing in type 1 diabetic rat by the synergistic effect of photobiomodulation therapy and conditioned medium. J Cell Biochem. 2019; 120:9906-16. 10.1002/jcb.28273.

        • Tomas D.M.
        • Paulette C.
        • Silvia B.B.
        • Claudia L.S.
        • Virgilio G.
        • Martha L.A.R.
        The role of bone marrow mesenchymal stromal cell derivatives in skin wound healing in diabetic mice.
        PLoS One. 2017; 12: e0177533
        • Chen S.
        • Wang H.
        • Su Y.
        • John J.V.
        • McCarthy A.
        • Wong S.L.
        • et al.
        Mesenchymal stem cell-laden, personalized 3D scaffolds with controlled structure and fiber alignment promote diabetic wound healing.
        Acta Biomater. 2020; 108: 153-167
        • Chen B.
        • Lu D.B.
        • Liang Z.W.
        • Jiang Y.Z.
        • Wang F.H.
        • Wu Q.N.
        • et al.
        Autologous bone marrow mesenchymal stem cell transplantation for treatment of diabetic foot following amplification in vitro.
        J Clin Rehabil Tissue Eng Res. 2009; 13: 6227-6230
        • Dash N.R.
        • Dash S.N.
        • Routray P.
        • Mohapatra S.
        • Mohapatra P.C.
        Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells.
        Rejuvenation Res. 2009; 12: 359-366
        • Debin L.
        • Youzhao J.
        • Ziwen L.
        • Xiaoyan L.
        • Zhonghui Z.
        • Bing C.
        Autologous transplantation of bone marrow mesenchymal stem cells on diabetic patients with lower limb ischemia.
        J Med Coll PLA. 2008; 23: 106-115
        • Jain P.
        • Perakath B.
        • Jesudason M.R.
        • Nayak S.
        The effect of autologous bone marrow-derived cells on healing chronic lower extremity wounds: results of a randomized controlled study.
        Ostomy Wound Manage. 2011; 57: 38-44
        • Kirana S.
        • Stratmann B.
        • Prante C.
        • Prohaska W.
        • Koerperich H.
        • Lammers D.
        • et al.
        Autologous stem cell therapy in the treatment of limb ischemia induced chronic tissue ulcers of diabetic foot patients.
        Int J Clin Pract. 2012; 66: 384-393
        • Lu D.
        • Chen B.
        • Liang Z.
        • Deng W.
        • Jiang Y.
        • Li S.
        • et al.
        Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial.
        Diabetes Res Clin Pract. 2011; 92: 26-36
        • Lu D.
        • Jiang Y.
        • Deng W.
        • Zhang Y.
        • Liang Z.
        • Wu Q.
        • et al.
        Long-Term Outcomes of BMMSC Compared with BMMNC for Treatment of Critical Limb Ischemia and Foot Ulcer in Patients with Diabetes.
        Cell Transplant. 2019; 28: 645-652
        • Humpert P.M.
        • Bärtsch U.
        • Konrade I.
        • Hammes H.P.
        • Morcos M.
        • Kasper M.
        • et al.
        Locally applied mononuclear bone marrow cells restore angiogenesis and promote wound healing in a type 2 diabetic patient.
        Exp Clin Endocrinol Diabetes. 2005; 113
        • Rogers L.C.
        • Bevilacqua N.J.
        • Armstrong D.G.
        The use of marrow-derived stem cells to accelerate healing in chronic wounds.
        Int Wound J. 2008; 5: 20-25
        • Dominici M.
        • Le Blanc K.
        • Mueller I.
        • Slaper-Cortenbach I.
        • Marini F.
        • Krause F.
        • et al.
        Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.
        Cytotherapy. 2006; 8
        • Maxson S.
        • Lopez E.A.
        • Yoo D.
        • Danilkovitch-Miagkova A.
        • Leroux M.A.
        Concise review: role of mesenchymal stem cells in wound repair.
        Stem Cells Transl Med. 2012; 1: 142-219
        • Kuo Y.R.
        • Wang C.T.
        • Cheng J.T.
        • Wang F.S.
        • Chiang Y.C.
        • Wang C.J.
        Bone marrow-derived mesenchymal stem cells enhanced diabetic wound healing through recruitment of tissue regeneration in a rat model of streptozotocin-induced diabetes.
        Plast Reconstr Surg. 2011; 128: 872-880
        • Hanson S.E.
        • Bentz M.L.
        • Hematti P.
        Mesenchymal stem cell therapy for nonhealing cutaneous wounds.
        Plast Reconstr Surg. 2010; 125: 510-556
        • Zhang Q.Z.
        • Su W.R.
        • Shi S.H.
        • Wilder-Smith P.
        • Xiang A.P.
        • Wong A.
        • et al.
        Human gingiva-derived mesenchymal stem cells elicit polarization of M2 macrophages and enhance cutaneous wound healing.
        Stem Cells. 2010; 28: 1856-1868
        • Németh K.
        • Leelahavanichkul A.
        • Yuen P.S.
        • Mayer B.
        • Parmelee A.
        • Doi K.
        • et al.
        Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production.
        Nat Med. 2009; 15: 42-59
        • Ren G.
        • Zhang L.
        • Zhao X.
        • Xu G.
        • Zhang Y.
        • Roberts A.I.
        • et al.
        Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide.
        Cell Stem Cell. 2008; 2: 141-150
        • Xu J.
        • Wu W.
        • Zhang L.
        • Dorset-Martin W.
        • Morris M.W.
        • Mitchell M.E.
        • et al.
        The role of MicroRNA-146a in the pathogenesis of the diabetic wound-healing impairment: correction with mesenchymal stem cell treatment.
        Diabetes. 2012; 61: 2906-2912
        • Hiasa K.
        • Ishibashi M.
        • Ohtani K.
        • Inoue S.
        • Zhao Q.
        • Kitamoto S.
        • et al.
        Gene transfer of stromal cell-derived factor-1α enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: next-generation chemokine therapy for therapeutic neovascularization.
        Circulation. 2004; 109: 2454-2461
        • Yamaguchi J.
        • Kusano K.F.
        • Masuo O.
        • Kawamoto A.
        • Silver M.
        • Murasawa S.
        • et al.
        Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization.
        Circulation. 2003; 107: 1322-2138
        • Grunewald M.
        • Avraham I.
        • Dor Y.
        • Bachar-Lustig E.
        • Itin A.
        • Jung S.
        • et al.
        VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells.
        Cell. 2006; 124: 175-189
        • Abid M.R.
        • Shih S.C.
        • Otu H.H.
        • Spokes K.C.
        • Okada Y.
        • Curiel D.T.
        • et al.
        A novel class of vascular endothelial growth factor-responsive genes that require forkhead activity for expression.
        J Biol Chem. 2006; 281: 35544-35553
        • Zheng J.
        • Wen Y.
        • Song Y.
        • Wang K.
        • Chen D.B.
        • Magness R.R.
        Activation of multiple signaling pathways is critical for fibroblast growth factor 2- and vascular endothelial growth factor-stimulated ovine fetoplacental endothelial cell proliferation.
        Biol Reprod. 2008; 78: 143-150
        • Arnold F.
        • West D.C.
        Angiogenesis in wound healing.
        J Pharmacol Ther. 1991; 52: 407-422
        • Li L.
        • Zhang Y.
        • Li Y.
        • Yu B.
        • Xu Y.
        • Zhao S.
        • et al.
        Mesenchymal stem cell transplantation attenuates cardiac fibrosis associated with isoproterenol-induced global heart failure.
        Transpl Int. 2008; 21: 1181-2119
        • Kim C.H.
        • Lee J.H.
        • Won J.H.
        • Cho M.K.
        Mesenchymal stem cells improve wound healing in vivo via early activation of matrix metalloproteinase-9 and vascular endothelial growth factor.
        J Korean Med Sci. 2011; 26: 726-733
        • Schievenbusch S.
        • Strack I.
        • Scheffler M.
        • Wennhold K.
        • Maurer J.
        • Nischt R.
        • et al.
        Profiling of anti-fibrotic signaling by hepatocyte growth factor in renal fibroblasts.
        Biochem Biophys Res Commun. 2009; 385: 55-61
        • Bevan D.
        • Gherardi E.
        • Fan T.P.
        • Edwards D.
        • Warn R.
        Diverse and potent activities of HGF/SF in skin wound repair.
        J Pathol. 2004; 203: 831-888
        • Shukla M.N.
        • Rose J.L.
        • Ray R.
        • Lathrop K.L.
        • Ray A.
        • Ray P.
        Hepatocyte growth factor inhibits epithelial to myofibroblast transition in lung cells via Smad7.
        Am J Respir Cell Mol Biol. 2009; 40: 643-653
        • Tian H.
        • Lu Y.
        • Shah S.P.
        • Hong S.
        14S, 21R-dihydroxydocosahexaenoic acid remedies impaired healing and mesenchymal stem cell functions in diabetic wounds.
        J Biol Chem. 2011; 286: 4443-4453
        • Sasaki M.
        • Abe R.
        • Fujita Y.
        • Ando S.
        • Inokuma D.
        • Shimizu H.
        Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type.
        J Immunol. 2008; 180: 2581-3257
        • Javazon E.H.
        • Keswani S.G.
        • Badillo A.T.
        • Crombleholme T.M.
        • Zoltick P.W.
        • Radu A.P.
        • et al.
        Enhanced epithelial gap closure and increased angiogenesis in wounds of diabetic mice treated with adult murine bone marrow stromal progenitor cells.
        Wound Repair Regen. 2007; 15: 350-439
        • Badillo A.T.
        • Redden R.A.
        • Zhang L.
        • Doolin E.J.
        • Liechty K.W.
        Treatment of diabetic wounds with fetal murine mesenchymal stromal cells enhances wound closure.
        Cell Tissue Res. 2007; 329: 301-311
        • Stepanovic V.
        • Awad O.
        • Jiao C.
        • Dunnwald M.
        • Schatteman G.C.
        Leprdb diabetic mouse bone marrow cells inhibit skin wound vascularization but promote wound healing.
        Circ Res. 2003; 92: 1247-1253
        • Carvalho A.B.
        • Quintanilha L.F.
        • Dias J.V.
        • Paredes B.D.
        • Mannheimer E.G.
        • Carvalho F.G.
        • et al.
        Bone marrow multipotent mesenchymal stromal cells do not reduce fibrosis or improve function in a rat model of severe chronic liver injury.
        Stem Cells. 2008; 26: 1307-1314
        • McLeod C.M.
        • Mauck R.L.
        On the origin and impact of mesenchymal stem cell heterogeneity: new insights and emerging tools for single cell analysis.
        Eur Cell Mater. 2017; 34
        • Kim I.
        • Bang S.I.
        • Lee S.K.
        • Park S.Y.
        • Kim M.
        • Ha H.
        Clinical implication of allogenic implantation of adipogenic differentiated adipose-derived stem cells.
        Stem Cells Transl Med. 2014; 3: 1312-1321
        • Villalvilla A.
        • Gomez R.
        • Roman-Blas J.A.
        • Largo R.
        • Herrero-Beaumont G.
        SDF-1 signaling: a promising target in rheumatic diseases.
        Expert Opin Ther Targets. 2014; 18: 1077-1087
        • Wang J.
        • Knaut H.
        Chemokine signaling in development and disease.
        Development. 2014; 141
        • Julier Z.
        • Park A.J.
        • Briquez P.S.
        • Martino M.M.
        Promoting tissue regeneration by modulating the immune system.
        Acta Biomater. 2017; 15: 13-28
        • Meng H.
        • Wang Z.
        • Wang W.
        • Li W.
        • Wu Q.
        • Lei X.
        • et al.
        Effect of osteopontin in regulating bone marrow mesenchymal stem cell treatment of skin wounds in diabetic mice.
        Diabetes Metab Res Rev. 2014; 30: 457-466