In this paper, we established a delayed wound healing model on diabetic rat to mimic the pathophysiology of clinical patients who suffered from diabetic foot ulcers. We also evaluated if transplantation of allogeneic bone marrow-derived mesenchymal stem cells could promote the delayed wound healing and investigated the possible underlying biological mechanisms and stem cell behavior involved in this process. The results showed that bone marrow-derived mesenchymal stem cells had a positive effect on delayed wound healing in diabetic rats. Intramuscular transplantation demonstrated the best efficacy. This effect is associated with granulation tissue formation, angiogenesis, cellular proliferation, and high vascular endothelial growth factor expression in wound tissues. In addition, bone marrow-derived mesenchymal stem cells have been shown to mobilize and find home for ischemic and wounded tissues to participate in the process of wound healing. Intramuscular transplantation of exogenous isogeneic stem cells may be suitable for clinical application in the treatment of diabetic foot ulcers although the safety of this therapy should be considered. 1. Introduction The incidence of diabetes mellitus is growing and reaching epidemic proportions worldwide [1]. The total number of diabetics is estimated to rise from 171 million in 2000 to 366 million in 2030 [2]. Diabetic foot ulcers (DFUs) are one of the most serious complications of diabetes. The lifetime risk of developing foot ulceration in persons with diabetes is as high as 25% [3]. Over 14–24% of these patients will have progressive disease that eventually leads to amputation [4]. In fact, complications of DFUs are the number one cause of nontraumatic lower extremity amputations [5], which is also associated with a high rate of morbidity and mortality with a 5-year survival rate as low as 31% for major limb amputees [6]. Wound healing is a complex process, which includes four overlapping phases: coagulation, inflammation, migration-proliferation, and remodeling [7]. Poor wound healing is a major issue in patients who suffer from DFUs. Peripheral vascular disease, trauma, infection, and neuropathy complicate the treatment of these wounds and thus necessitate a multidisciplinary approach [8]. Appropriate wound management varies mainly according to the cause of the wound, such as aggressive debridement, adequate pressure offloading, treatment of infection, hyperbaric oxygen therapy, bypass surgery for revascularization, and local dressings [9]. However, those concomitant or sequential therapeutic approaches
References
[1]
M. P. Khanolkar, S. C. Bain, and J. W. Stephens, “The diabetic foot,” QJM, vol. 101, no. 9, pp. 685–695, 2008.
[2]
S. Wild, G. Roglic, A. Green, R. Sicree, and H. King, “Global prevalence of diabetes: estimates for the year 2000 and projections for 2030,” Diabetes Care, vol. 27, no. 5, pp. 1047–1053, 2004.
[3]
N. Singh, D. G. Armstrong, and B. A. Lipsky, “Preventing foot ulcers in patients with diabetes,” Journal of the American Medical Association, vol. 293, no. 2, pp. 217–228, 2005.
[4]
“Consensus Development Conference on Diabetic Foot Wound Care. 7-8 April 1999, Boston, Massachusetts. American Diabetes Association,” Journal of the American Podiatric Medical Association, vol. 89, no. 9, pp. 475–483, 1999.
[5]
S. Miyajima, A. Shirai, S. Yamamoto, N. Okada, and T. Matsushita, “Risk factors for major limb amputations in diabetic foot gangrene patients,” Diabetes Research and Clinical Practice, vol. 71, no. 3, pp. 272–279, 2006.
[6]
E. Faglia, G. Clerici, J. Clerissi et al., “Early and five-year amputation and survival rate of diabetic patients with critical limb ischemia: data of a cohort study of 564 patients,” European Journal of Vascular and Endovascular Surgery, vol. 32, no. 5, pp. 484–490, 2006.
[7]
V. Falanga, “Wound healing and its impairment in the diabetic foot,” The Lancet, vol. 366, no. 9498, pp. 1736–1743, 2005.
[8]
S. Malhotra, E. Bello, and S. Kominsky, “Diabetic foot ulcerations: biomechanics, charcot foot, and total contact cast,” Seminars in Vascular Surgery, vol. 25, no. 2, pp. 66–69, 2012.
[9]
J. Apelqvist, “Diagnostics and treatment of the diabetic foot,” Endocrine, vol. 41, no. 3, pp. 384–397, 2012.
[10]
P. R. Cavanagh, B. A. Lipsky, A. W. Bradbury, and G. Botek, “Treatment for diabetic foot ulcers,” The Lancet, vol. 366, no. 9498, pp. 1725–1735, 2005.
[11]
Y. Wu, J. Wang, P. G. Scott, and E. E. Tredget, “Bone marrow-derived stem cells in wound healing: a review,” Wound Repair and Regeneration, vol. 15, supplement 1, pp. S18–S26, 2007.
[12]
Y. Wu, L. Chen, P. G. Scott, and E. E. Tredget, “Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis,” Stem Cells, vol. 25, no. 10, pp. 2648–2659, 2007.
[13]
J. Vojtassak, L. Danisovic, M. Kubes, et al., “Autologous biograft and mesenchymal stem cells in treatment of the diabetic foot,” Neuro Endocrinology Letters, vol. 27, supplement 2, pp. 134–137, 2006.
[14]
V. Falanga, S. Iwamoto, M. Chartier et al., “Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds,” Tissue Engineering, vol. 13, no. 6, pp. 1299–1312, 2007.
[15]
N. R. Dash, S. N. Dash, P. Routray, S. Mohapatra, and P. C. Mohapatra, “Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells,” Rejuvenation Research, vol. 12, no. 5, pp. 359–366, 2009.
[16]
X. Y. Jiang, D. B. Lu, and B. Chen, “Progress in stem cell therapy for the diabetic foot,” Diabetes Research and Clinical Practice, vol. 97, no. 1, pp. 43–50, 2012.
[17]
H. Li and x. Fu, “Mechanisms of action of mesenchymal stem cells in cutaneous wound repair and regeneration,” Cell and Tissue Research, vol. 348, no. 3, pp. 371–377, 2012.
[18]
B. Amann, C. Luedemann, R. Ratei, and J. A. Schmidt-Lucke, “Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease,” Cell Transplantation, vol. 18, no. 3, pp. 371–380, 2009.
[19]
V. Procházka, J. Gumulec, J. Chmelová et al., “Autologous bone marrow stem cell transplantation in patients with end-stage chronical critical limb ischemia and diabetic foot,” Vnitrni Lekarstvi, vol. 55, no. 3, pp. 173–178, 2009.
[20]
Y. Yang, T. Xia, W. Zhi et al., “Promotion of skin regeneration in diabetic rats by electrospun core-sheath fibers loaded with basic fibroblast growth factor,” Biomaterials, vol. 32, no. 18, pp. 4243–4254, 2011.
[21]
T. W. Lau, D. S. Sahota, C. H. Lau et al., “An in vivo investigation on the wound-healing effect of two medicinal herbs using an animal model with foot ulcer,” European Surgical Research, vol. 41, no. 1, pp. 15–23, 2008.
[22]
M. A. Elsharawy, M. Naim, and S. Greish, “Human CD34+ stem cells promote healing of diabetic foot ulcers in rats,” Interactive Cardiovasc Thoracic Surgery, vol. 14, no. 3, pp. 288–293, 2012.
[23]
N. Polisetti, V. G. Chaitanya, P. P. Babu, and G. K. Vemuganti, “Isolation, characterization and differentiation potential of rat bone marrow stromal cells,” Neurology India, vol. 58, no. 2, pp. 200–208, 2010.
[24]
M. Leiker, G. Suzuki, V. S. Iyer, J. M. Canty, and T. Lee, “Assessment of a nuclear affinity labeling method for tracking implanted mesenchymal stem cells,” Cell Transplantation, vol. 17, no. 8, pp. 911–922, 2008.
[25]
A. C. Júnior, M. A. Rodrigues, and V. D. Delfino, “An experimental model for the study of drug effects on cutaneous healing,” Acta Cirúrgica Brasileira, vol. 22, no. 4, pp. 317–321, 2007.
[26]
M. Galeano, B. Deodato, D. Altavilla et al., “Adeno-associated viral vector-mediated human vascular endothelial growth factor gene transfer stimulates angiogenesis and wound healing in the genetically diabetic mouse,” Diabetologia, vol. 46, no. 4, pp. 546–555, 2003.
[27]
K. J. Livak and T. D. Schmittgen, “Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method,” Methods, vol. 25, no. 4, pp. 402–408, 2001.
[28]
S. Maxson, E. A. Lopez, D. Yoo, et al., “Concise review: role of mesenchymal stem cells in wound repair,” Stem Cells Translational Medicine, vol. 1, no. 2, pp. 142–149, 2012.
[29]
Y. R. Kuo, C. T. Wang, J. T. Cheng, et al., “Bone marrow-derived mesenchymal stem cells enhanced diabetic wound healing through recruitment of tissue regeneration in a rat model of streptozotocin-induced diabetes,” Plastic and Reconstructive Surgery, vol. 128, no. 4, pp. 872–880, 2011.
[30]
S. E. Hanson, M. L. Bentz, and P. Hematti, “Mesenchymal stem cell therapy for nonhealing cutaneous wounds,” Plastic and Reconstructive Surgery, vol. 125, no. 2, pp. 510–516, 2010.
[31]
M. Sasaki, R. Abe, Y. Fujita, S. Ando, D. Inokuma, and H. Shimizu, “Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type,” Journal of Immunology, vol. 180, no. 4, pp. 2581–2587, 2008.
[32]
R. G. Harris, E. L. Herzog, E. M. Bruscia, J. E. Grove, J. S. van Arnam, and D. S. Krause, “Lack of a fusion requirement for development of bone marrow-derived epithelia,” Science, vol. 305, no. 5680, pp. 90–93, 2004.
[33]
Y. Wu, R. C. H. Zhao, and E. E. Tredget, “Concise review: bone marrow-derived stem/progenitor cells in cutaneous repair and regeneration,” Stem Cells, vol. 28, no. 5, pp. 905–915, 2010.
[34]
A. M. Hocking and N. S. Gibran, “Mesenchymal stem cells: paracrine signaling and differentiation during cutaneous wound repair,” Experimental Cell Research, vol. 316, no. 14, pp. 2213–2219, 2010.
[35]
M. Gnecchi, Z. Zhang, A. Ni, and V. J. Dzau, “Paracrine mechanisms in adult stem cell signaling and therapy,” Circulation Research, vol. 103, no. 11, pp. 1204–1219, 2008.
[36]
K. G. Harding, K. Moore, and T. J. Phillips, “Wound chronicity and fibroblast senescence—implications for treatment,” International Wound Journal, vol. 2, no. 4, pp. 364–338, 2005.
[37]
J. Campisi, “The role of cellular senescence in skin aging,” Journal of Investigative Dermatology Symposium Proceedings, vol. 3, no. 1, pp. 1–5, 1998.
[38]
P. Wang, Z. H. Xie, Y. J. Guo et al., “VEGF-induced angiogenesis ameliorates the memory impairment in APP transgenic mouse model of Alzheimer's disease,” Biochemical and Biophysical Research Communications, vol. 411, no. 3, pp. 620–626, 2011.
[39]
R. Roskoski Jr., “VEGF receptor protein-tyrosine kinases: structure and regulation,” Biochemical and Biophysical Research Communications, vol. 375, no. 3, pp. 287–291, 2008.
[40]
C. Hou, L. Shen, Q. Huang, et al., “The effect of heme oxygenase-1 complexed with collagen on MSC performance in the treatment of diabetic ischemic ulcer,” Biomaterials, vol. 34, no. 1, pp. 112–120, 2013.
[41]
E. J. Marrotte, D. D. Chen, J. S. Hakim, and A. F. Chen, “Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice,” The Journal of Clinical Investigation, vol. 120, no. 12, pp. 4207–4219, 2010.
[42]
R. W. Franz, A. Parks, K. J. Shah, T. Hankins, J. F. Hartman, and M. L. Wright, “Use of autologous bone marrow mononuclear cell implantation therapy as a limb salvage procedure in patients with severe peripheral arterial disease,” Journal of Vascular Surgery, vol. 50, no. 6, pp. 1378–1390, 2009.
[43]
J. L. Richard, C. Parer-Richard, J. P. Daures et al., “Effect of topical basic fibroblast growth factor on the healing of chronic diabetic neuropathic ulcer of the foot: a pilot, randomized, double-blind, placebo-controlled study,” Diabetes Care, vol. 18, no. 1, pp. 64–69, 1995.
[44]
D. H. Walter, H. Krankenberg, J. O. Balzer et al., “Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia a randomized-start, placebo-controlled pilot trial (PROVASA),” Circulation, vol. 4, no. 1, pp. 26–37, 2011.
[45]
P. Jain, B. Perakath, M. R. Jesudason, et al., “The effect of autologous bone marrow-derived cells on healing chronic lower extremity wounds: results of a randomized controlled study,” Ostomy Wound Manage, vol. 57, no. 7, pp. 38–44, 2011.
[46]
S. P. Bennett, G. D. Griffiths, A. M. Schor, G. P. Leese, and S. L. Schor, “Growth factors in the treatment of diabetic foot ulcers,” British Journal of Surgery, vol. 90, no. 2, pp. 133–146, 2003.
