Regenerative Medicine in Critical Limb Ischemia

Abstract

Critical limb ischemia (CLI) is commonly caused by atherosclerotic arterial obstruction or stenosis in the leg, as demonstrated by rest pain, skin ulcers and gangrene (Fontaine Ⅲ or Ⅳ), often fails to respond to conservative treatments, and carries a high risk for limb amputation, with a particularly dismal prognosis. Although surgical revascularization techniques may be used for certain CLI patients, such techniques are not indicated for most CLI patients due to the diffuse nature of the responsible lesions, distal location of the obstruction, or coexisting systemic comorbidities. For such CLI patients with no alternative treatments, the potential utility of cell therapies has been investigated. Indeed many clinical trials are being carried out by academic sectors, and their achievements will facilitate clinical development by pharmaceutical companies. In order to understand the situation regarding competitive international R&D of revascularization seeds for CLI, we surveyed the status of clinical trials. As a result, we identified 58 clinical trials on revascularization for CLI, with the majority in the early phase (＜phase Ⅱ: 82.7%). Revascularization seeds for CLI are in the development and competition phase, and promising seeds are expected to appear in the near future. In this review, we discuss how to develop optimal regenerative medicine concerning the selection of cell origin, cell type, combination with growth factor, and the influence of concomitant disease.

Human Stem Cells Overexpressing miR-21 Promote Angiogenesis in Critical Limb Ischemia by Targeting CHIP to Enhance HIF-1α Activity

“…Recently, gene therapy and cell‐based therapies for therapeutic angiogenesis in peripheral artery disease have attracted much attention . As mentioned before, angiogenic regeneration and formation can be elicited through the HIF‐1α/VEGF pathway .…”

Mesenchymal Stromal Cells Inhibit Inflammatory Lymphangiogenesis in the Cornea by Suppressing Macrophage in a TSG-6-Dependent Manner

“…22,23 Having such a perivascular location, MSCs have been shown to promote blood and lymphatic vessel formation and stability as support niche cells for vascular regeneration, by recruiting circulating vascular progenitor cells or by releasing pro-angiogenic factors. 10,[23][24][25] The effects of MSCs on vascular regeneration have been found to be beneficial for wound healing, [26][27][28] attenuation of limb ischemia, 29 or reperfusion of infarcted heart. 30 Apart from their effects on vascular cells, MSCs can modulate various immune cells including monocytes/macrophages.…”

Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells

“…Additionally, a recent hiPS derivation of EPCs using partially reprogrammed fibroblasts, demonstrated a quick reprogramming to ECs and the potential application for acute critical limb ischemia (11). There are applications in cell therapybased regenerative medicine, where sustained, durable, and functionally competent blood vessels are crucial, such as in longstanding ischemic (17), arterial, diabetic, or nonhealing ulcers. Lack of timely intervention thereof leads to nontraumatic limb amputation (18).…”