Potential risks of bone marrow cell transplantation into infarcted hearts

Abstract

Cellular replacement therapy has emerged as a novel strategy for the treatment of heart failure. The aim of our study was to determine the fate of injected mesenchymal stem cells (MSCs) and whole bone marrow (BM) cells in the infarcted heart. MSCs were purified from BM of transgenic mice and characterized using flow cytometry and in vitro differentiation assays. Myocardial infarctions were generated in mice and different cell populations including transgenic MSCs, unfractionated BM cells, or purified hematopoietic progenitors were injected. Encapsulated structures were found in the infarcted areas of a large fraction of hearts after injecting MSCs (22 of 43, 51.2%) and unfractionated BM cells (6 of 46, 13.0%). These formations contained calcifications and/or ossifications. In contrast, no pathological abnormalities were found after injection of purified hematopoietic progenitors ( IntroductionSevere heart failure is caused by an irreversible loss of cardiomyocytes and has a poor prognosis regardless of the underlying disease. 1 Since medical treatment is of only limited help, solid organ transplantation was considered until recently the only effective therapy. However, as organ availability decreases, there is an urgent need for alternative treatments. Studies in mice have suggested that myocardial infarctions can be repaired following transplantation of bone marrow (BM)-derived cells into the lesioned myocardium, either through generation of cardiomyocytes or angiogenesis. 2 An underlying assumption of this approach is that the environment will instruct as well as restrict the developmental fate of adult stem cells after their transplantation (for review see Laflamme and Murry 3 or Murry et al 4 ). However, the original findings in mice have recently been put into question, since we and others have demonstrated that BM-derived hematopoietic cells do not transdifferentiate into cardiomyocytes in the infarcted myocardium. [5][6][7] In this study, we focused on the potential of an enriched population of mesenchymal stem cells (MSCs) that are known to be present in the BM and are multipotent. 8 In contrast to hematopoietic progenitors, MSCs are easy to obtain and to expand in vitro and have therefore emerged as attractive candidates for cellular therapies in heart and other organs. 9,10 However, recent reports have questioned their "transdifferentiation" potential after injection into the myocardium and rather propose benefits via paracrine mechanisms. 11,12 Herein, we investigated and provide novel insights with regard to the fate of enriched populations of BM-derived MSCs as well as whole BM cells comprising both hematopoietic and mesenchymal progenitors after transplantation into the infarcted heart. Materials and methodsAll experiments were approved by the local ethics care committees at Bonn, Cologne, and Lund Universities. Cells for transplantation were isolated from transgenic C57Bl/6 mice expressing enhanced green fluorescent protein (EGFP) under control of the ␤-actin promoter. 13 Cell isolation and cultu...

Hippo Pathway Effectors Control Cardiac Progenitor Cell Fate by Acting as Dynamic Sensors of Substrate Mechanics and Nanostructure

“…19 Along with the occurrence of a severe inflammatory response, the loss in ECM compliance associated with myocardium ARTICLE www.acsnano.org C remodeling has been described as one of the main limitations to resident stem/progenitor cell activation and differentiation. 28,29 The effect of increased substrate stiffness on cardiomyocyte activity has been already reported by our group and others; 14,30 thus, we hypothesized that substrate stiffening could affect …”

Treatment of severe progressive systemic sclerosis with transplantation of mesenchymal stromal cells from allogeneic related donors: Report of five cases

“…We do not assume that MSC transplantation actually elicited the myocardial involvement since the first patient had clearly preexisting cardiac impairment and the second patient underwent autologous and allogeneic stem cell transplantation after MSC transplantation, thereby receiving drugs of known cardiac toxicity. However, it has been reported that MSC transplantation has led to the calcification of murine myocardium (12). This is probably the result of MSC differentiation into osteoclast-like cells.…”

Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics

“…However, matrix stiffening is more relevant for many biological events, including tissue development, wound healing and disease progression, such as fibrosis and tumour formation. For instance, fibrous scar tissue that develops after myocardial infarction is much stiffer than normal myocardium [17][18][19] , and mesenchymal stem cells (MSCs) differentiate down an osteogenic lineage and produce markers of bone when injected into infarct tissue in mice 20 . Recent evidence also suggests that matrix stiffening, which is generally regarded as an outcome of disease, may be a contributing factor in disease development.…”