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Angiogenic CD34 Stem Cell Therapy in Coronary Microvascular Repair-A Systematic Review.

ABSTRACT: Ischemia with non-obstructive coronary arteries (INOCA) is an increasingly recognized disease, with a prevalence of 3 to 4 million individuals, and is associated with a higher risk of morbidity, mortality, and a worse quality of life. Persistent angina in many patients with INOCA is due to coronary microvascular dysfunction (CMD), which can be difficult to diagnose and treat. A coronary flow reserve <2.5 is used to diagnose endothelial-independent CMD. Antianginal treatments are often ineffective in endothelial-independent CMD and thus novel treatment modalities are currently being studied for safety and efficacy. CD34⁺ cell therapy is a promising treatment option for these patients, as it has been shown to promote vascular repair and enhance angiogenesis in the microvasculature. The resulting restoration of the microcirculation improves myocardial tissue perfusion, resulting in the recovery of coronary microvascular function, as evidenced by an improvement in coronary flow reserve. A pilot study in INOCA patients with endothelial-independent CMD and persistent angina, treated with autologous intracoronary CD34⁺ stem cells, demonstrated a significant improvement in coronary flow reserve, angina frequency, Canadian Cardiovascular Society class, and quality of life (ESCaPE-CMD, NCT03508609). This work is being further evaluated in the ongoing FREEDOM (NCT04614467) placebo-controlled trial.

SUBMITTER: Rai B

PROVIDER: S-EPMC8151216 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleParacrine secretions seem to mediate therapeutic effects of human CD34+ stem cells locally transplanted in patients with myocardial and critical limb ischemia and in animal models. Earlier, we had discovered that paracrine secretion from human CD34+ cells contains proangiogenic, membrane-bound nanovesicles called exosomes (CD34Exo).ObjectiveHere, we investigated the mechanisms of CD34Exo-mediated ischemic tissue repair and therapeutic angiogenesis by studying their miRNA content and uptake.Methods and resultsWhen injected into mouse ischemic hindlimb tissue, CD34Exo, but not the CD34Exo-depleted conditioned media, mimicked the beneficial activity of their parent cells by improving ischemic limb perfusion, capillary density, motor function, and their amputation. CD34Exo were found to be enriched with proangiogenic miRNAs such as miR-126-3p. Knocking down miR-126-3p from CD34Exo abolished their angiogenic activity and beneficial function both in vitro and in vivo. Interestingly, injection of CD34Exo increased miR-126-3p levels in mouse ischemic limb but did not affect the endogenous synthesis of miR-126-3p, suggesting a direct transfer of stable and functional exosomal miR-126-3p. miR-126-3p enhanced angiogenesis by suppressing the expression of its known target, SPRED1, simultaneously modulating the expression of genes involved in angiogenic pathways such as VEGF (vascular endothelial growth factor), ANG1 (angiopoietin 1), ANG2 (angiopoietin 2), MMP9 (matrix metallopeptidase 9), TSP1 (thrombospondin 1), etc. Interestingly, CD34Exo, when treated to ischemic hindlimbs, were most efficiently internalized by endothelial cells relative to smooth muscle cells and fibroblasts, demonstrating a direct role of stem cell-derived exosomes on mouse endothelium at the cellular level.ConclusionsCollectively, our results have demonstrated a novel mechanism by which cell-free CD34Exo mediates ischemic tissue repair via beneficial angiogenesis. Exosome-shuttled proangiogenic miRNAs may signify amplification of stem cell function and may explain the angiogenic and therapeutic benefits associated with CD34+ stem cell therapy.

Project description:Background Microvascular angina (MVA) has received increasing attention and interest in recent years, but there are still some shortcomings in the diagnosis and treatments at current stage. In recent years, several studies have confirmed the efficacy of proprietary Chinese medicines (PCMs) in improving MVA symptoms; however, there is no systematic review and meta-analysis to comprehensively assess the efficacy of PCMs in this area. Objective Investigating the clinical efficacy of proprietary Chinese medicines for treating MVA and coronary microvascular function. Methods We looked up articles from January 1, 2012, to the present from eight databases. Then, we screened the literature and followed the 2019 version 2 of Cochrane risk of bias tool for systematic review. The Stata/SE 15.0 software was used for the meta-analysis. Results There are 21 studies, including 1,641 patients who were included in this review. According to the results, the combination of PCMs and conventional MVA treatment was able to further enhance clinical efficacy [RR = 1.28, 95% CI (1.20, 1.36), p < 0.001], prolong the time of duration on the treadmill exercise testing (TET) [SMD = 1.49, 95% CI (0.63, 2.36), p = 0.001] and improve levels of NO [SMD = −1.77 95% CI (−2.11, −1.43), p < 0.001]. At the same time, PCMs could also decrease the microvascular resistance index (IMR) [SMD = −1.79, 95% CI (−2.58, −1.00), p < 0.001)], serum level of hs-CRP [SMD = −1.21, 95% CI (−1.84, −0.58), p < 0.001] and ET-1 [SMD = −1.77 95% CI (−2.11, −1.43), p < 0.001]. Regards to medication safety, a total of 27 adverse events occurred, including 10 cases in the intervention group and 17 cases in the control group. Conclusion The study suggests that the combination of PCMs and conventional MVA treatment enhances clinical efficacy and could better improve coronary microvascular function. In the future, we expect more high-quality, randomized, double-blind clinical studies to validate the safety, and efficacy of PCMs to provide valuable evidence-based medicine (EBM) for the treatment of MVA with PCMs.

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Angiogenic CD34 Stem Cell Therapy in Coronary Microvascular Repair-A Systematic Review.

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