@article{78dbb0f49a2f45209e36989438d55024,
title = "Major improvement in wound healing through pharmacologic mobilization of stem cells in severely diabetic rats",
abstract = "Current therapeutic strategies for diabetic foot ulcer (DFU) have focused on developing topical healing agents, but few agents have controlled prospective data to support their effectiveness in promoting wound healing. We tested a stem cell mobilizing therapy for DFU using a combination of AMD3100 and low-dose FK506 (tacrolimus) (AF) in streptozocin-induced type 1 diabetic (T1DM) rats and type 2 diabetic Goto-Kakizaki (GK) rats that had developed peripheral artery disease and neuropathy. Here, we show that the time for healing back wounds in T1DM rats was reduced from 27 to 19 days, and the foot wound healing time was reduced from 25 to 20 days by treatment with AF (subcutaneously, every other day). Similarly, in GK rats treated with AF, the healing time on back wounds was reduced from 26 to 21 days. Further, this shortened healing time was accompanied by reduced scar and by regeneration of hair follicles. We found that AF therapy mobilized and recruited bone marrow–derived CD1331 and CD341 endothelial progenitor cells and Ym1/21 M2 macrophages into the wound sites, associated with enhanced capillary and hair follicle neogenesis. Moreover, AF therapy improved microcirculation in diabetic and neuropathic feet in GK rats. This study provides a novel systemic therapy for healing DFU.",
author = "Le Qi and Ahmadi, {Ali Reza} and Jinny Huang and Melissa Chen and Baohan Pan and Hiroshi Kuwabara and Kenichi Iwasaki and Wei Wang and Russell Wesson and Cameron, {Andrew M.} and Shusen Cui and James Burdick and Zhaoli Sun",
note = "Funding Information: Acknowledgments. The authors thank Dr. John Harmon and Dr. G. Melville Williams (Johns Hopkins University) for comments and advice on the study. Funding. This work was made possible by a Start-up fund from Surgery, Johns Hopkins Hospital, and a grant from MedRegen LLC. L.Q. was partially supported by the China Scholarship Council. Duality of Interest. J.B. is currently chief medical officer of MedRegen LLC. Z.S. is a cofounder of and holds equity in MedRegen LLC. Additionally, Z.S. is an inventor of technology and participates in research funded by MedRegen LLC that intends to further develop the technology. No other potential conflicts of interest relevant to this article were reported. Author Contributions. L.Q. performed the surgical excisional wound model, BMT, and histological studies. A.R.A., J.H., M.C., H.K., K.I., W.W., and R.W. gave animal treatment, evaluated the wounds, and analyzed data. B.P. evaluated the nociceptive intraepidermal nerve fibers in diabetic rats. A.M.C. and J.B. analyzed data and edited the manuscript. S.C. and Z.S. designed the study. Z.S. supervised the study, analyzed data, and wrote the manuscript. Z.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the 79th Scientific Sessions of the American Diabetes Association, San Francisco, CA, June 7–11, 2019. Publisher Copyright: {\textcopyright} 2020 by the American Diabetes Association.",
year = "2020",
month = apr,
day = "1",
doi = "10.2337/db19-0907",
language = "English (US)",
volume = "69",
pages = "699--712",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "4",
}