title: Increasing injection frequency enhances the survival of injected bone marrow derived mesenchymal stem cells in a critical limb ischemia animal model.
abstract: Critical limb ischemia (CLI) is one of the most severe forms of peripheral artery diseases, but current treatment strategies do not guarantee complete recovery of vascular blood flow or reduce the risk of mortality. Recently, human bone marrow derived mesenchymal stem cells (MSCs) have been reported to have a paracrine influence on angiogenesis in several ischemic diseases. However, little evidence is available regarding optimal cell doses and injection frequencies. Thus, the authors undertook this study to investigate the effects of cell dose and injection frequency on cell survival and paracrine effects. MSCs were injected at 106or 105per injection (high and low doses) either once (single injection) or once in two consecutive weeks (double injection) into ischemic legs. Mice were sacrificed 4 weeks after first injection. Angiogenic effects were confirmedin vitroandin vivo, and M2 macrophage infiltration into ischemic tissues and rates of limb salvage were documented. MSCs were found to induce angiogenesis through a paracrine effectin vitro, and were found to survive in ischemic muscle for up to 4 weeks dependent on cell dose and injection frequency. In addition, double high dose and low dose of MSC injections increased vessel formation, and decreased fibrosis volumes and apoptotic cell numbers, whereas a single high dose did not. Our results showed MSCs protect against ischemic injury in a paracrine manner, and suggest that increasing injection frequency is more important than MSC dosage for the treatment CLI.
authors.affiliation: Cardiology, Gachon University Gil Medical Center, Incheon 21565, Korea.
authors.forename: Woong Chol
authors.initials: WC
authors.lastname: Kang
authors.affiliation: Cardiology, Gachon University Gil Medical Center, Incheon 21565, Korea.
authors.forename: Pyung Chun
authors.initials: PC
authors.lastname: Oh
authors.affiliation: Cardiology, Gachon University Gil Medical Center, Incheon 21565, Korea.
authors.forename: Kyounghoon
authors.initials: K
authors.lastname: Lee
authors.affiliation: Cardiology, Gachon University Gil Medical Center, Incheon 21565, Korea.
authors.forename: Taehoon
authors.initials: T
authors.lastname: Ahn
authors.affiliation: Department of Anatomy and Cell Biology, Graduate School of Medicine, Gachon University, Incheon 21936, Korea.; Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea.
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Byun
keywords: Bone marrow derived mesenchymal stem cells; Critical limb ischemia; High MSCs dose injection; High frequency injection