Profoundly Reduced Neovascularization Capacity of Bone Marrow Mononuclear Cells Derived From Patients With Chronic Ischemic Heart Disease

Abstract

Background— Cell therapy with bone marrow–derived stem/progenitor cells is a novel option for improving neovascularization and cardiac function in ischemic heart disease. Circulating endothelial progenitor cells in patients with coronary heart disease are impaired with respect to number and functional activity. However, whether this impairment also extends to bone marrow–derived mononuclear cells (BM-MNCs) in patients with chronic ischemic cardiomyopathy (ICMP) is unclear. Methods and Results— BM-MNCs were isolated from bone marrow aspirates in 18 patients with ICMP (ejection fraction, 38±11%) and 8 healthy control subjects (controls). The number of hematopoietic stem/progenitor cells (CD34 + /CD133 + ), CD49d + (VLA-4) cells, and CXCR4 + cells did not differ between the 2 groups. However, the colony-forming capacity of BM-MNCs from patients with ICMP was significantly lower compared with BM-MNCs from healthy controls (37.3±25.0 versus 113.8±70.4 granulocyte-macrophage colony-forming units; P =0.009). Likewise, the migratory response to stromal cell–derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) was significantly reduced in BM-MNCs derived from patients with ICMP compared with BM-MNCs from healthy controls (SDF-1, 46.3±26.2 versus 108.6±40.4 cells/microscopic field, P <0.001; VEGF, 34±24.2 versus 54.8±29.3 cells/microscopic field, P =0.027). To assess the in vivo relevance of these findings, we tested the functional activity of BM-MNCs to improve neovascularization in a hindlimb animal model using nude mice. Two weeks after ligation of the femoral artery and intravenous injection of 5×10 5 BM-MNCs, laser Doppler–derived relative limb blood flow in mice treated with BM-MNCs from patients with ICMP was significantly lower compared with mice treated with BM-MNCs from healthy controls (0.45±0.14 versus 0.68±0.15; P <0.001). The in vivo neovascularization capacity of BM-MNCs closely correlated with the in vitro assessment of SDF-1–induced migration ( r =0.78; P <0.001) and colony-forming capacity ( r =0.74; P <0.001). Conclusions— BM-MNCs isolated from patients with ICMP have a significantly reduced migratory and colony-forming activity in vitro and a reduced neovascularization capacity in vivo despite similar content of hematopoietic stem cells. This functional impairment of BM-MNCs from patients with ICMP may limit their therapeutic potential for clinical cell therapy.

Mesenchymal stem cells are superior to angiogenic growth factor genes for improving myocardial performance in the mouse model of acute myocardial infarction

“…Heeschen et al have demonstrated that patients with chronic ischemic heart disease have profoundly reduced neovascularization capacity in their bone marrow mononuclear cells [35]. Furthermore, Rauscher et al have demonstrated the progressive progenitor cell deficits in older animals [36].…”

Adiponectin as a tissue regenerating hormone: more than a metabolic function

“…In the bone, fAd promotes the differentiation of mesenchymal progenitors into osteoblasts [77]. In the endothelium, fAd promotes the enhancement of proliferation and the migration of keratinocytes [88], ameliorates wound repair in adiponectin-deficient and diabetic db/db mice [88] and increases the recruitment of endothelial cell precursors [78] differentiation towards a mature endothelium, adhesive properties [86], proliferative rate [87,88], and capacity to be incorporated into vascular structures [89]. Recent findings suggest that T2 DM and subsequent oxidative damage impede the interaction between the vascular wall and normal ePC through a mechanism that could be reversed by heme-oxygenase-1, fAd, and phospho-AMPK [82].…”

Neovascularization Potential of Blood Outgrowth Endothelial Cells From Patients With Stable Ischemic Heart Failure Is Preserved

“…One of the major concerns when envisioning autologous (progenitor/stem) cell therapy in cardiovascular medicine, is the presumed dysfunctional progenitor cell phenotype in older and diseased patients burdened with risk factors, as evidenced for early outgrowth EPCs of monocytic origin (also known as circulating angiogenic cells),9, 10, 11, 12 CD133 + /VEGFR2+ circulating EPCs,10, 13 colony‐forming‐unit EPCs (CFU‐Hill),13, 14 bone‐marrow–derived mononuclear cells (MNCs)15 and hematopoietic stem cells 11…”