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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:637.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Therapeutic Angiogenesis Using Tissue Engineered Human Smooth Muscle Cell Sheets

Kyoko Hobo; Tatsuya Shimizu; Hidekazu Sekine; Toshiharu Shin’oka; Teruo Okano; Hiromi Kurosawa

From the Department of Cardiovascular Surgery (K.H., T. Shin’oka, H.K.), The Heart Institute of Japan, and the Institute of Advanced Biomedical Engineering and Science (T. Shimizu, H.S., T.O.), Tokyo Women’s Medical University, Tokyo, Japan.

Correspondence to Hiromi Kurosawa, MD, PhD, Department of Cardiovascular Surgery, The Heart Institute of Japan, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail kurosawa{at}hij.twmu.ac.jp

Objective— Peripheral arterial disease (PAD) can have severe consequences on patient mortality and morbidity. In contrast to approaches using growth factor administration or isolated cell transplantation, we attempted to develop an alternative method for ischemic therapy using the transplantation of tissue engineered cell sheets with angiogenic potential.

Methods and Results— Human smooth muscle cell (SMC) and fibroblast cell (FbC) sheets were harvested from temperature-responsive culture dishes and transplanted into ischemic hind limbs of athymic rats. ELISA showed significantly increased in vitro secretion of angiogenic factors by SMCs in comparison to FbCs. Twenty-one days after transplantation, laser doppler analysis demonstrated significantly increased blood perfusion in the SMC group. Perfusion with Indian ink and immunohistochemistry also revealed significantly greater numbers of functional capillaries in the SMC group. Finally, cell tracing experiments revealed that some SMCs from the transplanted cell sheets migrated into the ischemic tissues, contributing to newly formed vessels.

Conclusions— SMC sheet transplantation allows for controlled and localized delivery of cells that possess angiogenic potential directly to ischemic tissues. Through the secretion of angiogenic factors, as well as cell migration and integration with newly formed vessels, SMC sheet transplantation provides an effective method for the revascularization of ischemic tissues.

We developed tissue engineered cell sheets which can be transplanted en bloc to provide a stable and localizable biological effect in ischemic tissue. Smooth muscle cell sheets transplantation result in significantly enhanced angiogenesis and blood perfusion through the secretion of angiogenic factors and integration with newly formed vessels.

Key Words: smooth muscle cell • cell sheet • angiogenesis