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(Circulation. 2006;113:2413-2424.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Topical Sonic Hedgehog Gene Therapy Accelerates Wound Healing in Diabetes by Enhancing Endothelial Progenitor Cell–Mediated Microvascular Remodeling

Jun Asai, MD; Hideya Takenaka, MD, PhD; Kengo F. Kusano, MD, PhD; Masaaki Ii, MD, PhD; Corinne Luedemann, BS; Cynthia Curry, BS; Elizabeth Eaton, BS; Atsushi Iwakura, MD, PhD; Yoshiaki Tsutsumi, MD, PhD; Hiromichi Hamada, MD, PhD; Saburo Kishimoto, MD, PhD; Tina Thorne, MS; Raj Kishore, PhD; Douglas W. Losordo, MD

From the Division of Cardiovascular Research and Medicine, St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass (J.A., K.F.K., M.I., C.L., C.C., E.E., A.I., Y.T., H.H., R.K., D.W.L.); Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (J.A., H.T., S.K.); and Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan (M.I.).

Correspondence to Douglas W. Losordo, MD, Division of Cardiovascular Research and Medicine, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA, 02135. E-mail douglas.losordo{at}tufts.edu

Received June 23, 2005; de novo received November 21, 2005; revision received March 7, 2006; accepted March 10, 2006.

Background— Sonic hedgehog (Shh) is a prototypical morphogen known to regulate epithelial-mesenchymal interaction during embryonic development. Recent observations indicate that exogenous administration of Shh can induce angiogenesis and may accelerate repair of ischemic myocardium and skeletal muscle. Because angiogenesis plays a pivotal role in wound repair, we hypothesized that activation of the hedgehog pathway may promote a favorable effect on microvascular remodeling during cutaneous wound healing and thereby accelerate wound closure. Because diabetes is associated with impaired wound healing, we tested this hypothesis in a diabetic model of cutaneous wound repair.

Methods and Results— In Ptc1-LacZ mice, cutaneous injury resulted in LacZ expression, indicating that expression of the Shh receptor Patched was induced and therefore that the Shh signaling pathway was intact postnatally and upregulated in the process of wound repair. In diabetic mice, topical gene therapy with the use of naked DNA encoding for Shh resulted in significant local gene expression and acceleration of wound recovery. The acceleration in wound healing was notable for increased wound vascularity. In bone marrow transplantation models, the enhanced vascularity of the wound was shown to be mediated, at least in part, by enhanced recruitment of bone marrow–derived endothelial progenitor cells. In vitro, Shh promoted production of angiogenic cytokines from fibroblasts as well as proliferation of dermal fibroblasts. Furthermore, Shh directly promoted endothelial progenitor cell proliferation, migration, adhesion, and tube formation.

Conclusions— These findings suggest that a simple strategy of topically applied Shh gene therapy may have significant therapeutic potential for enhanced wound healing in patients with impaired microcirculation such as occurs in diabetes. (Circulation. 2006;113:2413-2424.)

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