Therapeutic strategies for cell-based neovascularization in critical limb ischemia

Abstract

Critical limb ischemia (CLI) causes severe ischemic rest pain, ulcer, and gangrene in the lower limbs. In spite of angioplasty and surgery, CLI patients without suitable artery inflow or enough vascular bed in the lesions are often forced to undergo amputation of a major limb. Cell-based therapeutic angiogenesis has the potential to treat ischemic lesions by promoting the formation of collateral vessel networks and the vascular bed. Peripheral blood mononuclear cells and bone marrow-derived mononuclear cells are the most frequently employed cell types in CLI clinical trials. However, the clinical outcomes of cell-based therapeutic angiogenesis using these cells have not provided the promised benefits for CLI patients, reinforcing the need for novel cell-based therapeutic angiogenesis strategies to cure untreatable CLI patients. Recent studies have demonstrated the possible enhancement of therapeutic efficacy in ischemic diseases by preconditioned graft cells. Moreover, judging from past clinical trials, the identification of adequate transplant timing and responders to cell-based therapy is important for improving therapeutic outcomes in CLI patients in clinical settings. Thus, to establish cell-based therapeutic angiogenesis as one of the most promising therapeutic strategies for CLI patients, its advantages and limitations should be taken into account.

Keywords: Cell-based therapeutic angiogenesis; Clinical trials; Combination therapy; Critical limb ischemia; Hypoxic preconditioning; Peripheral blood mononuclear cells.

Fig. 1

Schematic representation of hypoxic preconditioning of peripheral blood mononuclear cells (PBMNCs). Hypoxic preconditioning of PBMNCs at 2% O₂ and 33 °C for 24 h. Cell retention, cell survival, and angiogenic potency are increased by this simple method, improving efficacy of cell-based therapy in ischemic conditions

Fig. 2

A patient with right foot atherosclerotic gangrene after injection of preconditioned cells. a The angiography revealed a poor vascular bed in the right foot (circle). b Location of the gangrene-infected amputation site of the Lisfranc in the right foot. Skin perfusion pressure (SPP) was 27 mm Hg pre-treatment. c Hypoxic preconditioned peripheral blood mononuclear cells were transplanted into 54 points (1 × 10⁷/0.1 mL/point) in ischemic tissue (5.4 × 10⁸ cells). d SPP increased to 59 mmHg 7 days after treatment, however necrosis and infection gradually worsened

Fig. 3

Combination therapy using hypoxic preconditioning and apelin. Hypoxic preconditioning and ischemic conditions upregulate the APJ receptor in peripheral blood mononuclear cells (PBMNCs) and vascular smooth muscle cells (VSMCs). Preconditioned PBMNCs receive exogenous apelin, leading to the secretion of platelet-derived growth factor (PDGF)-BB. Exogenous apelin induces upregulation of PDGF receptor-β in ischemic VSMCs. Subsequently, VSMCs are activated to mature newly formed vessels in ischemic tissue