Recruitment and retention of human autologous CD34+ CD117+ CD133+ bone marrow stem cells to infarcted myocardium followed by directed vasculogenesis: Novel strategy for cardiac regeneration

Abstract

BackgroundOngoing clinical trials, in regenerative therapy of patients suffering from myocardial infarctions, rely primarily upon administration of bone marrow stem cells to the infarcted zones. Unfortunately, low retention of these cells, to the therapeutic delivery sites, reduces effectiveness of this strategy; thus it has been identified as the most critical problem for advancement of cardiac regenerative medicine.Specific aimsThe specific aim of this work was three-fold: (1) to isolate highly viable populations of human, autologous CD34+, CD117+, and CD133+ bone marrow stem cells; (2) to bioengineer heterospecific, tetravalent antibodies and to use them for recruiting of the stem cells to regenerated zones of infarcted myocardium; (3) to direct vasculogenesis of the retained stem cells with the defined factors.Patients methodsCardiac tissue was biopsied from the hearts of the patients, who were receiving orthotopic heart transplants after multiple cardiac infarctions. This tissue was used to engineer fully human in vitro models of infarcted myocardium. Bone marrow was acquired from these patients. The marrow cells were sorted into populations of cells displaying CD34, CD117, and CD133. Heterospecific, tetravalent antibodies were bioengineered to bridge CD34, CD117, CD133 displayed on the stem cells with cardiac myosin of the infarcted myocardium. The sorted stem cells were administered to the infarcted myocardium in the in vitro models.ResultsAdministration of the bioengineered, heterospecific antibodies preceding administration of the stem cells greatly improved the stem cells’ recruitment and retention to the infarcted myocardium. Treatment of the retained stem cells with vascular endothelial growth factor and angiopoietin efficiently directed their differentiation into endothelial cells, which expressed vascular endothelial cadherin, platelet/endothelial cell adhesion molecule, claudin, and occludin, while forming tight and adherens junctions.ConclusionsThis novel strategy improved retention of the patients’ autologous bone marrow cells to the infarcted myocardium followed by directed vasculogenesis. Therefore, it is worth pursuing it in support of the ongoing clinical trials of cardiac regenerative therapy.

Heme Oxygenase-1/Carbon Monoxide System and Embryonic Stem Cell Differentiation and Maturation into Cardiomyocytes

“…These findings put the HO-1/CO system and heme catabolism at a regulatory checkpoint in ES cell differentiation and cardiomyocyte maturation. Prior work suggesting that stem cell use, perhaps including marrowderived cells, may contribute to repair of infarcts in excess of cell engraftment may indicate paracrine effects (26,36,45). Thus, agents that activate HO-1 in ES cell differentiation in vitro or in vivo may be expected to contribute to regenerative cell therapy in patients with advanced heart disease.…”

Thrombospondin-1-Derived Peptide RFYVVMWK Improves the Adhesive Phenotype of CD34+ Cells from Atherosclerotic Patients with Type 2 Diabetes

“…However, cardiovascular risk factors such as T2D were associated with dysfunctional progenitor cells, including impaired adhesiveness 5,6 , which undermines their therapeutic value in autologous cell therapies 20 . CD34 + PBMC recruitment to damaged vessels is a crucial step to initiate the process of vascular repair and neovascularization 9 . In ex vivo settings, we observed a lower basal adhesion of T2D CD34 + cells to vitronectin–collagen matrix compared to the non-T2D CD34 + cells.…”

“…The ability of CD34 + cells to adhere and engraft onto damaged vessel walls is crucial to initiate neovascularization 9 . During this process, activated platelets are instrumental in targeting CD34 + cell recruitment to injured vessels via stromal cell-derived factor-1 (SDF-1α) secretion and chemotaxism 10 .…”

Stimulating endogenous cardiac repair

“…Tetravalent antibodies have also been employed for the same goal. These antibodies were generated to target an epitope on apoptotic cardiac myocytes, CD34, CD133, and c-kit cells (Malecki et al, 2013 ). This approach significantly improved the recruitment and retention of the various stem cell populations to the damaged myocardium.…”