Placenta-derived mesenchymal stem cells for allogenic cardiac cell therapy

Objective: Mesenchymal stem cells (MSC) may be useful for cardiac cell therapy. While preparation of autologous MSC products is time consuming, allogenic immunotolerant MSC products would be available for off-the-shelf application. We sought to investigate the cardiac regeneration potential of a novel, placenta derived human MSC product (pMSC) in a mouse model of myocardial infarction. Methods: pMSC were isolated from the decidua and chorionic vilii of human donor placentas and grown as 2D cultures and expanded in a 3D bioreactor system including a fibrous matrix. Cryopreserved cells were thawed and immediately used for transplantation. Myocardial infarction was induced in C57Bl/6 mice by permanent LAD ligation, and pMSC were immediately injected in the infarct border zone (n=9). After 4 weeks, transthoracic echocardiography was performed, followed by cardiac MRI. Then, mice were sacrificed and the hearts prepared for histologic examination. In control mice, cell-free medium was injected (n=8), and sham-operate animals underwent thoracotomy only. Results: The surface marker phenotype of pMSC resembled that of typical somatic MSC (CD45-, CD34-, CD73+, CD90+) except that they were CD271-. Upon xenogenic and allogenic in vivo injection, no relevant immune response was noted. Compared to control mice, pMSC treated hearts had significantly smaller infarct size (6±5% vs. 31±8%) and greater regional LV wall thickness 1.9±0.3 vs. 0.34±0.2mm, associated with downregulation of remodelling-associated periostin. pMSC treatment led to pronounced arteriogenesis in the infarct border zone (13±5 vs. 7±4 arteries/hpf, p=0.01), and there was evidence of angiogenesis stimulation (71±23 vs. 43±18 CD31+ capillaries/hpf, p<0.05)). Transthoracic echocardiography under stress conditions (average heart rate 589±67 bpm) demonstrated better contractile function in pMSC treated mice (LVEF 42±8% vs, 33±6%, p<0.05). As measured by MRI under general anesthesia (heart rate 301±42bpm), however, there was no difference in LV dimension and contractile function (LVEF 32±9 vs. 31±7%, p=0.3; LVEDV 0.11±0.03 vs. 0.11±0.05ml, p=0.7, LVESV 0.08±0.02 vs. 0.08±0.03ml, p=0.6). Conclusion: Human pMSC should be suitable for evaluation in clinical pilot trials of cardiac cell therapy. They induce beneficial effects on remodelling and blood vessel growth, associated with improved contractile function under stress conditions.