Abstract
Background: Bone Marrow Mononuclear Cells (BM-MNC) constitute a promising alternative for the treatment of Chronic Limb-Threatening ischemia (CLTI), a disease characterized by extensive blockade of peripheral arteries, clinically presenting as excruciating pain at rest and ischemic ulcers which may lead to gangrene and amputation. BM-MNC implantation has shown to be efficient in promoting angiogenesis and ameliorating ischemic symptoms in CLTI patients. However, the variability seen between clinical trials makes necessary a further understanding of the mechanisms of action of BM-MNC, and moreover, to improve trial characteristics such as endpoints, inclusion/exclusion criteria or drug product compositions, in order to implement their use as stem-cell therapy.Materials: Herein, the effect of REX-001, a human-BM derived cell suspension enriched for mononuclear cells, granulocytes and CD34+ cells, has been assessed in a murine model of CLTI. In addition, a REX-001 placebo solution containing BM-derived red blood cells (BM-RBCs) was also tested. Thus, 24 h after double ligation of the femoral artery, REX-001 and placebo were administrated intramuscularly to Balb-c nude mice (n:51) and follow-up of ischemic symptoms (blood flow perfusion, motility, ulceration and necrosis) was carried out for 21 days. The number of vessels and vascular diameter sizes were measured within the ischemic tissues to evaluate neovascularization and arteriogenesis. Finally, several cell-tracking assays were performed to evaluate potential biodistribution of these cells.Results: REX-001 induced a significant recovery of blood flow by increasing vascular density within the ischemic limbs, with no cell translocation to other organs. Moreover, cell tracking assays confirmed a decrease in the number of infused cells after 2 weeks post-injection despite on-going revascularization, suggesting a paracrine mechanism of action.Conclusion: Overall, our data supported the role of REX-001 product to improve revascularization and ischemic reperfusion in CLTI.
Highlights
Chronic limb-threatening ischemia (CLTI) results from the narrowing and obstruction of major arteries of the limb, usually correlated with the formation of atherosclerotic plaques (Conte and Vale, 2018; Uccioli et al, 2018)
Bone Marrow Mononuclear Cells (BM-MNC) constitute a promising alternative for the treatment of Chronic Limb-Threatening ischemia (CLTI), a disease characterized by extensive blockade of peripheral arteries, clinically presenting as excruciating pain at rest and ischemic ulcers which may lead to gangrene and amputation
In this study we investigated the regenerative effect of REX001, an adult human bone marrow (BM)-derived cell suspension enriched for MNC, when injected in a murine model of CLTI, in order to understand the mechanisms potentially involved in BM-MNC induced revascularization within the ischemic tissues, as well as to evaluate REX-001 potential bio-distribution after intramuscular administration
Summary
Chronic limb-threatening ischemia (CLTI) results from the narrowing and obstruction of major arteries of the limb, usually correlated with the formation of atherosclerotic plaques (Conte and Vale, 2018; Uccioli et al, 2018). CLTI patients suffer from chronic rest pain, ischemic ulcers which may lead to gangrene, and an eventual amputation of toes or extremities. Amputation rates are unacceptably high in CLTI patients, typically exceeding 15–20% at 1 year of intervention and can vary according to additional comorbidities (Duff et al, 2019) such as diabetes mellitus (DM), which elevates the amputation rate to 50% (Spreen et al, 2016). Bone Marrow Mononuclear Cells (BM-MNC) constitute a promising alternative for the treatment of Chronic Limb-Threatening ischemia (CLTI), a disease characterized by extensive blockade of peripheral arteries, clinically presenting as excruciating pain at rest and ischemic ulcers which may lead to gangrene and amputation. Several cell-tracking assays were performed to evaluate potential biodistribution of these cells
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