Improved Arteriogenesis with Simultaneous Skeletal Muscle Repair in Ischemic Tissue by SCL+ Multipotent Adult Progenitor Cell Clones from Peripheral Blood

Abstract

Background: The CD34– murine stem cell line RM26 cloned from peripheral blood mononuclear cells has been shown to generate hematopoietic progeny in lethally irradiated animals. The peripheral blood-derived cell clones expresses a variety of mesodermal and erythroid/myeloid transcription factors suggesting a multipotent differentiation potential like the bone marrow-derived ‘multipotent adult progenitor cells’ (MAP-C). Methods: SCL+ CD34– RM26 cells were transfused intravenously into mice suffering from chronic hind-limb ischemia, evaluating the effect of stem cells on collateral artery growth and simultaneous skeletal muscle repair. Results: RM26 cells are capable of differentiating in vitro into endothelial cells when cultured on the appropriate collagen matrix. Activation of the SCL stem cell enhancer (SCL+) is mediated through the binding to two Ets and one GATA site and cells start to express milieu- and growth condition-dependent levels of the endothelial markers CD31 (PECAM) and Flt-1 (VEGF-R1). Intravenously infused RM26 cells significantly improved the collateral blood flow (arteriogenesis) and neo-angiogenesis formation in a murine hind-limb ischemia transplant model. Although transplanted RM26 cells did not integrate into the growing collateral arteries, cells were found adjacent to local arteriogenesis, but instead integrated into the ischemic skeletal muscle exclusively in the affected limb for simultaneous tissue repair. Conclusion: These data suggest that molecularly primed hem-/mesangioblast-type adult progenitor cells can circulate in the peripheral blood improving perfusion of tissues with chronic ischemia and extending beyond the vascular compartment.

Multipotent adult progenitor cells sustain function of ischemic limbs in mice

“…This is in agreement with the observation that cells with high fusion capability mainly reside in the stromal fraction, while only a small fraction of the hematopoietic lineage is fusigenic (34). Other nonmuscle-derived cell types have shown the potential to contribute to SkMBs in ischemic muscle, e.g., CD34 + or CD34 + KDR + cord blood cells (10,13), the immortalized CD34 -R26 cell line generated from peripheral blood (35), or ADSCs (36).…”

Organ-injury-induced reactivation of hemangioblastic precursor cells

“…Interestingly, Brunet de la Grange et al 47 have revealed a major role for SCL in specification of adult hematopoietic myeloid progenitors, a type of hematopoietic cell that has been recently shown to stimulate angiogenesis in adult tissues via secretion of angiogenic growth factors. 48 Indeed, Huss et al 49 showed that intravenous infusion of SCL( þ ) multipotent adult progenitor cell clones in a hind-limb ischemia transplant model supported muscle repair via enhanced local arteriogenesis rather than induction of new blood vessel formation. In this regard, further characterization, purification and functional analyses of specific SCL 3 0 En cell subsets could be informative.…”

Redox-Dependent Mechanisms in Coronary Collateral Growth: The “Redox Window” Hypothesis

“…Vascular endothelial growth factor (VEGF) mediates many cellular responses involved in collateral growth, including cell survival, proliferation, and migration (121). The actions of VEGF on collateral growth appear to be mediated by signaling through the VEGFR1 (Flt-1) and VEGFR2 (Flk-1, KDR) receptors (2,11,44,121). Although more is known about Flk than Flt signaling, recently the role of Flt has been appreciated in ischemic preconditioning (66,100).…”