Abstract
The aim of this research is to compare the capabilities of Adipose tissue mesenchymal stem cells (AT-MSCs) and bone marrow mesenchymal stem cells (BM-MSCs) in the treatment of diabetic male mice with CLI model. Supernatants were collected from C57BL/6 mice isolated AT-MSCs and BM-MSCs, afterward their effects on human umbilical vein endothelial (HUVEC) migration potential were evaluated. Diabetes mellitus type 1 was induced by streptozotocin injection. Diabetic mice with CLI model were divided into three groups and injected with AT-MSCs, BM-MSCs, or PBS then the efficacy of them was assessed. Survival of MSCs was analysed by SRY-specific gene. The conditioned medium of AT-MSCs and BM-MSCs stimulated HUVECs migration and the donor cells were detected till 21 day in two groups. BM-MSCs and AT-MSCs improved significantly functional recovery and ischemia damage. Neovascularization in ischemic muscle was significantly higher in mice treated with AT-MSCs and BM-MSCs and they improved muscle regeneration. In vivo and in vitro findings show that AT-MSCs and BM-MSCs transplantation could be proposed as a promising therapy to promote angiogenesis and muscle regeneration through secretion of proangiogenic factors, cytokines and growth factors in diabetic mice with CLI model wherein blood supply is insufficient and disrupted.
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Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- CLI:
-
Critical limb ischemia
- PAD:
-
Peripheral arterial disease
- MSCs:
-
Mesenchymal stem cells
- AT-MSC:
-
Adipose tissue mesenchymal stem cell
- BM-MSCs:
-
Bone marrow mesenchymal stem cells
- HUVECs:
-
Humanumbilical vein endothelial cell
- MVD:
-
Microvessel density
- DM:
-
Diabetes mellitus
- VEGF:
-
Vascular endothelial growth factor
- STZ:
-
Streptozotocin
- PBS:
-
Phosphate-buffered saline
- DMEM:
-
Dulbecco’s modified Eagle’s medium
- FBS:
-
Fetal bovine serum
- IP:
-
Intraperitoneal
- IM:
-
Intramuscular
- H&E:
-
Hematoxylin and eosin
- IHC:
-
Immunohistochemical
- PFA:
-
Paraformaldehyde
- TBS:
-
Buffered Saline
- DAB:
-
Diaminobenzidine tetrahydrochloride
- SD:
-
Standard deviation
- RMANOVA:
-
Two-way analysis of variance test with repeated measurements
References
Adolfsson E, Helenius G, Friberg Ö, Samano N, Frøbert O, Johansson K (2020) Bone marrow-and adipose tissue-derived mesenchymal stem cells from donors with coronary artery disease; growth, yield, gene expression and the effect of oxygen concentration. Scand J Clin Lab Invest 80(4):1–9
Anderson P, Carrillo-Gálvez AB, García-Pérez A, Cobo M, Martín F (2013) CD105 (endoglin)-negative murine mesenchymal stromal cells define a new multipotent subpopulation with distinct differentiation and immunomodulatory capacities. PLoS ONE 8:e76979
Beugels J, De Munter J, Van der Hulst R, Kramer B, Wolters E (2019) Efficacy of different doses of human autologous adult bone mar-row stem cell transplantation on angiogenesis in an immune deficient rat model with hind limb ischemia. J Stem Cell Res Dev Ther 5:S1002
Brenes RA, Jadlowiec CC, Bear M, Hashim P, Protack CD, Li X, Lv W, Collins MJ, Dardik A (2012) Toward a mouse model of hind limb ischemia to test therapeutic angiogenesis. J Vasc Surg 56:1669–1679
Carstens MH, Zelaya M, Calero D, Rivera C, Correa D (2020) Adipose-derived stromal vascular fraction (SVF) cells for the treatment of non-reconstructable peripheral vascular disease in patients with critical limb ischemia: a 6-year follow-up showing durable effects. Stem Cell Res 49:102071
Chen L, Okeke E, Ayalew D, Wang D, Shahid L, Dokun AO (2017) Modulation of miR29a improves impaired post-ischemic angiogenesis in hyperglycemia. Exp Biol Med 242:1432–1443
Cleary M, Narcisi R, Focke K, Van der Linden R, Brama P, van Osch G (2016) Expression of CD105 on expanded mesenchymal stem cells does not predict their chondrogenic potential. Osteoarthr Cartil 24:868–872
Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC (2009) Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res 12:359–366
Dubský M, Jirkovska A, Bem R, Nemcova A, Fejfarova V, Jude EB (2017) Cell therapy of critical limb ischemia in diabetic patients–State of art. Diabetes Res Clin Pract 126:263–271
Fan W, Sun D, Liu J, Liang D, Wang Y, Narsinh KH, Li Y, Qin X, Liang J, Tian J (2012) Adipose stromal cells amplify angiogenic signaling via the VEGF/mTOR/Akt pathway in a murine hindlimb ischemia model: a 3D multimodality imaging study. PLoS ONE 7(9):e45621
Fikry EM, Safar MM, Hasan WA, Fawzy HM, El-Denshary EEDS (2015) Bone marrow and adipose-derived mesenchymal stem cells alleviate methotrexate-induced pulmonary fibrosis in rat: comparison with dexamethasone. J Biochem Mol Toxicol 29:321–329
Fu X, Liu G, Halim A, Ju Y, Luo Q, Song G (2019) Mesenchymal stem cell migration and tissue repair. Cells 8:784
Hioki H, Miyashita Y, Miura T, Ebisawa S, Motoki H, Izawa A, Tomita T, Koyama J, Ikeda U (2015) Prognostic improvement by multidisciplinary therapy in patients with critical limb ischemia. Angiol 66:187–194
Kaushik R, Sree B, Attri AK (2002) Spontaneous auto-amputation of the foot in a case of diabetes, atherosclerosis and gangrene. J Indian Med Assoc 100:573–574
Khajeh S, Razban V, Talaei-Khozani T, Soleimani M, Asadi-Golshan R, Dehghani F, Ramezani A, Mostafavi-Pour Z (2018) Enhanced chondrogenic differentiation of dental pulp-derived mesenchymal stem cells in 3D pellet culture system: effect of mimicking hypoxia. Biologia 73:715–726
Kohli N, Al-Delfi IR, Snow M, Sakamoto T, Miyazaki T, Nakajima H, Uchida K, Johnson WE (2019) CD271-selected mesenchymal stem cells from adipose tissue enhance cartilage repair and are less angiogenic than plastic adherent mesenchymal stem cells. Sci Rep 9:1–12
Lauvrud AT, Kelk P, Wiberg M, Kingham PJ (2017) Characterization of human adipose tissue-derived stem cells with enhanced angiogenic and adipogenic properties. J Tissue Eng Regen Med 11:2490–2502
Liang L, Li Z, Ma T, Han Z, Du W, Geng J, Jia H, Zhao M, Wang J, Zhang B (2017) Transplantation of human placenta-derived mesenchymal stem cells alleviates critical limb ischemia in diabetic nude rats. Cell Transplant 26:45–61
Liew A, O’Brien T (2012) Therapeutic potential for mesenchymal stem cell transplantation in critical limb ischemia. Stem Cell Res Ther 3:28
Liu J, Hao H, **a L, Ti D, Huang H, Dong L, Tong C, Hou Q, Zhao Y, Liu H (2015) Hypoxia pretreatment of bone marrow mesenchymal stem cells facilitates angiogenesis by improving the function of endothelial cells in diabetic rats with lower ischemia. PLoS ONE 10:e0126715
López Y, Lutjemeier B, Seshareddy KM, Trevino E, Sue HK, Musch IT, Borgarelli ML, Weiss M (2013) Wharton’s jelly or bone marrow mesenchymal stromal cells improve cardiac function following myocardial infarction for more than 32 weeks in a rat model: a preliminary report. Curr Stem Cell 8:46–59
Lotfy A, Salama M, Zahran F, Jones E, Badawy A, Sobh M (2014) Characterization of mesenchymal stem cells derived from rat bone marrow and adipose tissue: a comparative study. Int J Stem Cells 7:135
Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, Xu J, Wu Q, Zhang Z, **e B (2011) 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 92:26–36
Ma N, Cheng H, Lu M, Liu Q, Chen X, Yin G, Zhu H, Zhang L, Meng X, Tang Y (2015) Magnetic resonance imaging with superparamagnetic iron oxide fails to track the long-term fate of mesenchymal stem cells transplanted into heart. Sci Rep 5:1–9
Mohamed-Ahmed S, Fristad I, Lie SA, Suliman S, Mustafa K, Vindenes H, Idris SB (2018) Adipose-derived and bone marrow mesenchymal stem cells: a donor-matched comparison. Stem Cell Res Ther 9:168
Mottaghi S, Larijani B, Sharifi AM (2012) Apelin 13: a novel approach to enhance efficacy of hypoxic preconditioned mesenchymal stem cells for cell therapy of diabetes. Med Hypotheses 79:717–718
Parikh PP, Liu Z-J, Velazquez OC (2017) A molecular and clinical review of stem cell therapy in critical limb ischemia. Stem Cells Int 2017:1–10
Razban V, Khajeh S, Lotfi AS, Mohsenifar A, Soleimani M, Khoshdel A, Hashemi E (2014) Engineered heparan sulfate-collagen IV surfaces improve human mesenchymal stem cells differentiation to functional hepatocyte-like cells. J Biomater Tissue Eng 4:811–822
Russell KC, Phinney DG, Lacey MR, Barrilleaux BL, Meyertholen KE, O’Connor KC (2010) In vitro high-capacity assay to quantify the clonal heterogeneity in trilineage potential of mesenchymal stem cells reveals a complex hierarchy of lineage commitment. Stem Cells 28:788–798
Sherman AB, Gilger BC, Berglund AK, Schnabel LV (2017) Effect of bone marrow-derived mesenchymal stem cells and stem cell supernatant on equine corneal wound healing in vitro. Stem Cell Res Ther 8:120
Shu J, Santulli G (2018) Update on peripheral artery disease: Epidemiology and evidence-based facts. Atherosclerosis 275:379–381
Song P, Rudan D, Zhu Y, Fowkes FJ, Rahimi K, Fowkes FGR, Rudan I (2019) Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob Health 7:e1020–e1030
Tebebi PA, Kim SJ, Williams RA, Milo B, Frenkel V, Burks SR, Frank JA (2017) Improving the therapeutic efficacy of mesenchymal stromal cells to restore perfusion in critical limb ischemia through pulsed focused ultrasound. Sci Rep 7:41550
Volpe CMO, Villar-Delfino PH, Dos Anjos PMF, Nogueira-Machado JA (2018) Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis 9:1–9
Vu NB, Phi LT, Dao TT-T, Le HT-N, Van Pham P (2016) Adipose derived stem cell transplantation is better than bone marrow mesenchymal stem cell transplantation in treating hindlimb ischemia in mice. Biomed Res Ther 3:46
Wu Y, Chen L, Scott PG, Tredget EE (2007) Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells 25:2648–2659
Acknowledgements
The present study was financially supported by Shahid Sadoughi University of Medical Sciences, Yazd, Iran and Shiraz University of Medical Sciences, Shiraz, Iran. Also, the authors would like to thank the Research Consulting Center of Shiraz University of Medical Sciences (RCC) for their assistance in statistical analysis.
Funding
This work was supported by Shahid Sadoughi University of Medical Sciences Foundation (5984).
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SLAY: Conceptualization, Methodology, Investigation, Data curation, Project administration, Writing - original draft. PN: Conceptualization, Methodology, Investigation, Data curation. MS: Supervision, Writing - review & editing, Data curation, Validation, Funding acquisition. SMBT: Supervision, Writing - review & editing, Funding acquisition. SD: Methodology, Investigation, Data curation. HN: Data curation, Validation. ML: Data curation, Validation. VR: Supervision, Writing - review & editing, Data curation, Validation. The authors read and approved the final manuscript.
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All methods were performed in accordance with the regulations and guidelines approved by the ethics committee of Shahid Sadoughi University of Medical Sciences (IR.SSU.MEDICINE.REC.1397.031).
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Asadi-Yousefabad, SL., Nammian, P., Sheikhha, M.H. et al. Comparative study of mouse adipose- and bone marrow mesenchymal stem cells in diabetic model with critical limb ischemia. Cell Tissue Bank 23, 923–936 (2022). https://doi.org/10.1007/s10561-022-10007-7
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DOI: https://doi.org/10.1007/s10561-022-10007-7