Current Status of Angiogenic Cell Therapy and Related Strategies Applied in Critical Limb Ischemia

Abstract

Critical limb ischemia (CLI) constitutes the most severe form of peripheral arterial disease (PAD), it is characterized by progressive blockade of arterial vessels, commonly correlated to atherosclerosis. Currently, revascularization strategies (bypass grafting, angioplasty) remain the first option for CLI patients, although less than 45% of them are eligible for surgical intervention mainly due to associated comorbidities. Moreover, patients usually require amputation in the short-term. Angiogenic cell therapy has arisen as a promising alternative for these "no-option" patients, with many studies demonstrating the potential of stem cells to enhance revascularization by promoting vessel formation and blood flow recovery in ischemic tissues. Herein, we provide an overview of studies focused on the use of angiogenic cell therapies in CLI in the last years, from approaches testing different cell types in animal/pre-clinical models of CLI, to the clinical trials currently under evaluation. Furthermore, recent alternatives related to stem cell therapies such as the use of secretomes, exosomes, or even microRNA, will be also described.

Keywords: angiogenesis; arteriogenesis; cell therapy; critical limb ischemia; neovascularization; secretomes.

Figure 1

Overview of angiogenic cell therapy for Critical Limb Ischemia (CLI).

Figure 2

Schematic representation of femoral artery ligation (FAL) strategies usually applied to create PAD/CLI models, from the lowest (left) to the highest (right) severity models of the disease. A representative image of the FAL strategy followed in our research group is also shown [41,47]. Legend: ➀ Iliac artery, ➁ Iliacofemoral artery, ➂ Internal iliac artery, ➃ Pudendoepigastric trunk, ➄ Femoral artery and its branches (lateral circumflex and proximal caudal), ➅ Superficial caudal epigastric artery, ➆ Popliteal artery, and ➇ Saphenous artery. Arterial anatomy information was based on Kochi et al. [48].

Figure 3

Mechanisms of neovascularization. (a) Schematic representation of the circulatory system in which angiogenesis and arteriogenesis processes are represented. (b) Representative immunohistochemistry image of blood vessels detected in the low back muscle of a CLI mouse [47], to evaluate vascular density and diameter size using anti-smooth muscle α-actin (α-SMA, red) antibody.