By Temple University School of Podiatric Medicine Journal Review Club

Editor's note: This post is part of the Temple University School of Podiatric Medicine (TUSPM) journal review club blog series. In each blog post, a TUSPM student will review a journal article relevant to wound management and related topics and provide their evaluation of the clinical research therein.

Article Title: Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer

Authors: Cao Y, Gang X, Wang G

Journal: J Diabetes Res. 2017;2017:9328347.

Reviewed by: Sai Vemula, class of 2020, Temple University School of Podiatric Medicine

Introduction

A diabetic foot ulcer (DFU) is one of the most common complications of diabetes mellitus and presents a serious challenge worldwide because of its chronic, non-healing nature. These ulcers affect more than a quarter of U.S. patients with diabetes. Furthermore, these individuals are at twice the risk for amputations compared with non-diabetic individuals. The economic burden of the treatment of these conditions is a huge challenge to the health care realm. The traditional treatments for DFUs are ineffective, with a cure rate of approximately 30%.

Diabetic Foot Ulcer Risk Factors

Methods

Mesenchymal stem cells (MSCs) have been identified as the main source of regenerative therapy to treat DFUs because of the wide applicative potential of these cells, their ability to self-renew, and their wound healing capabilities. MSCs can be found in various tissues such as bone marrow, umbilical cord, adipose tissue, and placenta, to name a few. This research reviewed various studies that discussed autologous versus allogeneic MSCs obtained from different cell types and the pro and cons of these cells in terms of wound healing. Bone marrow is the most common and most easily accessible source of MSCs. Bone marrow does not stimulate an immune reaction and thus is very safe when it is delivered intramuscularly. However, with age, the potential for differentiation weakens. Bone marrow MSCs (BM-MSCs) stimulate diabetic wound healing by increasing migration, angiogenesis, and re-epithelialization.

Results

When it came to allogeneic versus autologous BM-MSCs, the allogeneic BM-MSCs were able to express various factors to migrate to the wound area, adhere to the endothelial cells, promote angiogenesis, and thicken granulation. Furthermore, a study showed these allogenic BM-MSCs also reduced duration of wound healing in DFUs on the plantar skin of rats. In contrast, the autologous BM-MSCs were unable to enhance migration in diabetic wounds. The researchers speculated that this effect was likely the result of the diabetic microenvironment (hyperglycemia and inflammation), which reduced the number of MSCs and their homing capability. When it came to the efficacy of the clinical trials, six weeks after intramuscular injection of autologous BM-MSCs, wound size decreased substantially and dermal vascularity increased while normal renal function and liver enzymes were maintained. A 24-week follow-up examination showed painless walking and significant improvement in total carbon dioxide, the ankle-brachial index, and limb perfusion. Umbilical cord blood–derived MSCs (UCB-MSCs) are morphologically analogous to BM-MSCs, with added benefits of anti-inflammatory activity, long viability, and shortened doubling time. However, a phase I study showed some adverse effects: diarrhea, oral ulcerations, and increased serum creatinine levels, not to mention the cost of preserving cord blood.

Adipose-derived MSCs (AMSCs) also had similarities to BM-MSCs, with the added benefit that they could be transferred as silk fibroin patches. These patches could be prepared and stored for extended durations. MSCs derived from other tissues (umbilical cord, placental, amniotic fluid, and gingival) were shown to have characteristics similar to those of BM-MSCs, with a few unique benefits of their own. Human gingival MSCs were shown to have the greatest advantage for avoiding the ethical problems associated with MSC clinical application, and furthermore, they produced similar healing results in hypoxic environments.

Conclusion

All studies have demonstrated the benefits of specific MSC cell types with certain unique characteristics that make them superior to BM-MSCs. Nevertheless, more data need to be collected to confirm these benefits, and until then BM-MSCs will be used as the gold standard. There is a lack of conclusive evidence on whether autologous MSCs are better than allogeneic MSCs. Clinical trials of allogeneic MSCs are increasing to ascertain the immunological profile that provides the best wound healing.

About the Author

Sai Vemula is a third-year podiatric medical student at Temple University School of Podiatric Medicine (TUSPM) in Philadelphia, Pennsylvania. He graduated from the University of California Berkeley with a Bachelor of Arts in molecular and cell biology. Sai did research at the University of California San Francisco and went on to complete a Master of Biomedical Science in stem cell biology at Rutgers New Jersey Medical School. In the fall of 2017, he matriculated at TUSPM with a merit scholarship. He is currently the Vice President of the Journal Society and Founder/Director of Temple’s social media organization. Dr. James McGuire is the director of the Leonard S. Abrams Center for Advanced Wound Healing and an associate professor of the Department of Podiatric Medicine and Orthopedics at the Temple University School of Podiatric Medicine in Philadelphia.