Myoblasts and Embryonic Stem Cells Differentially Engraft in a Mouse Model of Genetic Dilated Cardiomyopathy

Abstract

The functional and architectural benefits of embryonic stem cells (ESC) and myoblasts (Mb) transplantations into infarcted myocardium have been investigated extensively. Whereas ESC repopulated fibrotic areas and contributed to myocardial regeneration, Mb exerted their effects through paracrine secretions and scar remodeling. This therapeutic perspective, however, has been less explored in the setting of nonischemic dilated cardiomyopathies (DCMs). Our aim was to compare the integration and functional efficacy of ESC committed to cardiac fate by bone morphogenic protein 2 (BMP-2) pretreatment and Mb used as gold standard following their transplantation into the myocardium of a mouse model of laminopathy exhibiting a progressive and lethal DCM. After 4 and 8 weeks of transplantation, stabilization was observed in Mb-transplanted mice (P = 0.008) but not in groups of ESC-transplanted or medium-injected animals, where the left ventricular fractional shortening (LVFS) decreased by 32 ± 8% and 41 ± 8% respectively. Engrafted differentiated cells were consistently detected in myocardia of mice receiving Mb, whereas few or no cells were detected in the hearts of mice receiving ESC, except in two cases where teratomas were formed. These data suggest that committed ESC fail to integrate in DCM where scar tissue is absent to provide the appropriate niche, whereas the functional benefits of Mb transplantation might extend to nonischemic cardiomyopathy.

Skeletal Muscle Laminopathies: A Review of Clinical and Molecular Features

“…Stem cell treatment may represent a therapeutic option. Recently, Catelain et al [ 80 ] injected bone morphogenic protein 2-committed embryonic stem cells (ESCs) and myoblasts at four sites on the anterior-lateral wall of the left ventricle of a mouse model of dilated cardiomyopathy caused by LMNA mutation ( Lmna H222P/H222P mouse). After four and eight weeks of transplantation, few or no ESCs were detected in the heart, whereas muscle cells were observed together with a stabilization and improvement of heart function.…”

Exogenous connexin43‐expressing autologous skeletal myoblasts ameliorate mechanical function and electrical activity of the rabbit heart after experimental infarction

“…Interestingly, we observed some stabilization of LVEF in the Sham and SM/WT groups. We suppose that this stabilization could be achieved by mobilization of endogenous stem cells to the infarction zone that was mechanically injured by transplantation procedure and/or due to paracrine secretions and scar remodelling (Catelain et al 2013). Histological examination confirmed survival and incorporation of transplanted SMs in the infarction zone.…”

“…We suppose that this stabilization could be achieved by mobilization of endogenous stem cells to the infarction zone that was mechanically injured by transplantation procedure and/or due to paracrine secretions and scar remodelling (Catelain et al 2013). The expression of exogenous Cx43EGFP was crucial for obtaining this positive effect because in the control series of experiments (MI group), after infarction, LVEF continued to decrease within 3 months of observation.…”

Preclinical Advances of Therapies for Laminopathies

“…In 2013, Catelain et al compared transplantation efficiency of murine embryonic stem cells (ESC) induced into cardiac lineage, and a murine myoblast cell line (D7LNB1) considered at that time as “gold-standard” for cell-based therapy, into the LV wall of Lmna H222P / H222P mouse, a KI mouse model reproducing a mutation found in EDMD patients and mainly responsible for DCM in homozygous mice [ 60 ]. Myoblast engraft had a greater transplantation efficacy and improved cardiac functions (stabilization of LV fractional shortening), whereas ESCs failed to integrate in the myocardium of Lmna H222P / H222P mice [ 61 ]. Clearly, more research is needed in order to find the best cell type to use for cell therapy in the heart.…”