A Transformed Cell Population Derived from Cultured Mesenchymal Stem Cells has no Functional Effect after Transplantation into the Injured Heart

Abstract

Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent cells characterized by their selfrenewal and differentiation potential. Accumulating clinical and preclinical evidence indicate MSCs are a promising cell source for regenerative medical therapies. However, undesirable immortalization, spontaneous transformation, and tumorigenic potential from long-term cultured MSCs have been reported in human and mouse. We report rat MSCs isolated from young donors could undergo transformation in early passage culture. We aimed to characterize the transformed population and determine their therapeutic effects after intracardiac transplantation in the infarcted myocardium. MSCs were isolated from bone marrow of Lewis rats according to standard protocols and cultured under standard conditions. Phenotype of growing cells was assessed by flow cytometry. Following acute myocardial infarction in rats, cells were delivered by intracardiac injection. Cardiac functions were assessed by pressure-volume loops. Infarction size and pathologic effects were evaluated after 6 weeks. The abnormal colonies were detected in culture as early at passage 3. They were noted to appear as distinctly different morphology from typical MSCs, which changed from a normal elongated spindle shape to a compact abnormal morphology. They exhibited rapid cell proliferation. Some subclones lost contact inhibition of cell division and formed multilayer aggregates. Chromosomal instability was detected. They were devoid of surface markers CD29, CD44, CD90, and CD117. Furthermore, there was no significant improvement on infarction size and cardiac function 6 weeks after cell transplantation. Our study highlights the need for establishment of biosafety criteria in regulating cultureexpanded MSCs to achieve the full clinical therapeutic benefits.

Labeling Human Embryonic Stem Cell-Derived Cardiomyocytes with Indocyanine Green for Noninvasive Tracking with Optical Imaging: An FDA-Compatible Alternative to Firefly Luciferase

“…When compared to cardiac progenitors derived from human mesenchymal stem cells (hMSC), hESC-CMs have a distinct advantage because their in vitro differentiation model closely resembles in vivo cardiac development at a structural and electrophysiological level. Few studies, however, currently demonstrate this potential for hMSC (4,11,14,19).…”

Osteosarcoma: From Molecular Biology to Mesenchymal Stem Cells

“…Transformed murine MSCs exhibit a compact morphology, demonstrate anchorage-independent growth, lack contact inhibition and form multiple layers in culture. This is in contrast to the spindle-shaped single layer growth characteristics of MSCs [72][73][74][75]. The proliferation rates of transformed murine MSCs have been shown to be increased and genetic and molecular signalling alterations underlie these changes [72,76,77].…”

“…This is in contrast to the spindle-shaped single layer growth characteristics of MSCs [72][73][74][75]. The proliferation rates of transformed murine MSCs have been shown to be increased and genetic and molecular signalling alterations underlie these changes [72,76,77]. Increased chromosome number beyond the usual 40 acrocentric chromosomes have been demonstrated in transformed murine MSCs by multiple authors [72,73,78].…”

“…The proliferation rates of transformed murine MSCs have been shown to be increased and genetic and molecular signalling alterations underlie these changes [72,76,77]. Increased chromosome number beyond the usual 40 acrocentric chromosomes have been demonstrated in transformed murine MSCs by multiple authors [72,73,78]. Additionally, Matushansky et al [79] showed that inactivation of the Wnt pathway in transformed MSCs gave rise to a cell population with a similar appearance to that of malignant ibrous histiocytoma.…”

Immunologic and Inflammatory Reactions to Exogenous Stem Cells

“…Moreover, stem cells themselves can produce various immunomodulatory signaling factors, including both proinflammatory and anti-inflammatory molecules (33,34). The effects of exogenously administered stem cells and precursor cells on the evolution of myocardial infarction have been studied in mouse and rat models (1,2,13,19,22,(45)(46)(47)(48). In most of these studies, stem cells were delivered to syngeneic mice or rats, or xenogeneic stem cells (including those from humans) were used in severely immunosuppressed mice or rats, such as nude or SCID mice.…”