Autologous Mesenchymal Stem Cells Mobilize cKit ⁺ and CD133 ⁺ Bone Marrow Progenitor Cells and Improve Regional Function in Hibernating Myocardium

Abstract

Rationale: Mesenchymal stem cells (MSCs) improve function after infarction, but their mechanism of action remains unclear, and the importance of reduced scar volume, cardiomyocyte proliferation, and perfusion is uncertain.Objective: The present study was conducted to test the hypothesis that MSCs mobilize bone marrow progenitor cells and improve function by stimulating myocyte proliferation in collateral-dependent hibernating myocardium. Methods and Results: Swine with chronic hibernating myocardium received autologous intracoronary MSCs (icMSCs; Ϸ44؋106 cells, n‫)01؍‬ 4 months after instrumentation and were studied up to 6 weeks later. Physiological and immunohistochemical findings were compared with untreated hibernating animals (n‫,)7؍‬ sham-normal animals (n‫,)5؍‬ and icMSC-treated sham-normal animals (n‫. Key Words: mesenchymal stem cells Ⅲ hibernating myocardium Ⅲ bone marrow progenitor cells M esenchymal stem cells (MSCs) can repair a variety of tissues after injury 1 and are currently being used in clinical trials to treat patients with cardiovascular disease. 2 Nevertheless, their precise mechanism of action and the role of myocyte regeneration versus angiogenesis are controversial. Most preclinical investigation has focused on animal models of myocardial infarction in which intravenous, intramyocardial, and intracoronary administration of MSCs have been demonstrated to reduce infarct size and improve left ventricular (LV) function in both acute and chronic infarction. [3][4][5][6][7][8][9][10][11][12][13] Although early studies demonstrated the ability of autologous and allogeneic MSCs to differentiate into vessels, 8,14 smooth muscle, 14 and cardiac muscle, 15,16 the quantitative extent of MSC differentiation into a cardiac cellular phenotype has been small and inconsistent with measured reductions in infarct volume. 4,8,11 Recent investigations have hypothesized that MSCs effect cardiac repair through a paracrine mechanism that stimulates proliferation of endogenous myocytes, but in vivo studies quantifying the magnitude of myocyte proliferation are limited. Most analyses focus on the small rim of border zone tissue between normal and infarcted myocardium rather than larger remote regions or areas at risk of ischemia. 5,9,[17][18][19][20][21][22] Recently, we demonstrated that pravastatin can mobilize cKit ϩ and CD133 ϩ bone marrow progenitor cells (BMPCs). 23 The BMPCs localized in the heart and were accompanied by improved myocardial function in swine, with hibernating myocardium devoid of infarction in the absence of an increase in myocardial perfusion. Although BMPC mobilization had no effect on myocyte proliferation in the normal heart, it increased the frequency of myocytes in the proliferative phase of the cell cycle in diseased hearts and increased myocyte nuclear density with small myocytes that suggested that endogenous myocyte proliferation was stimulated. 23 Likewise, studies with skeletal muscle injection of porcine MSCs into Syrian hamsters 24 and MSCs that overexpressed insulin-like ...

Regenerating new heart with stem cells

“…However, this notion has been challenged by several examples of transition from one cell type to another or, more unexpectedly, from one cell lineage to another lineage (67)(68)(69)(70). The unanticipated plasticity of adult HSCs to generate cells beyond their own tissue boundary became the driving force of a series of studies in which HSCs were implemented experimentally to restore the necrotic myocardium after infarction (71)(72)(73)(74)(75)(76)(77)(78).…”

Intracoronary Infusion of Allogeneic Mesenchymal Precursor Cells Directly After Experimental Acute Myocardial Infarction Reduces Infarct Size, Abrogates Adverse Remodeling, and Improves Cardiac Function

“…On the contrary, infusion of lower cell numbers did not hamper coronary flow in previous experiments. Valina et al 22 infused only 2 million MSCs directly after AMI, and Suzuki et al 23 infused 15 million MSCs per coronary artery in hibernating myocardium, both without any flow-related side-effects. Also, in a study by Johnston et al 24 , infusion of 10 million cardiosphere-derived cells (20 micrometer in diameter) after AMI was deemed safe, whereas 25 million cells or more caused significant infarctions.…”

Insights Into Signaling in Cell-Based Therapy for Heart Disease

“…146 Although it has been shown that MSCs differentiate directly into cardiomyocytes, 26,34 the majority remain as MSCs and generate cell to cell interactions with host cardiomyocytes, stimulating endogenous cardiomyocyte turnover and CSC differentiation. 26,34,147 In addition to stimulating myocyte turnover and progenitor cell recruitment, 148 endogenous CSCs also promote repair through direct remuscularization 27 and these effects are enhanced by MSCs. Although some findings suggest that resident CSCs contribute only minimally to cardiac regeneration, 149 others have demonstrated that this is a variable process which is significantly enhanced after cell-cell contact with MSCs.…”