title: Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor-like state through partial cell fusion and mitochondria transfer.
abstract: Because stem cells are often found to improve repair tissue including heart without evidence of engraftment or differentiation, mechanisms underlying wound healing are still elusive. Several studies have reported that stem cells can fuse with cardiomyocytes either by permanent or partial cell fusion processes. However, the respective physiological impact of these two processes remains unknown in part because of the lack of knowledge of the resulting hybrid cells. To further characterize cell fusion, we cocultured mouse fully differentiated cardiomyocytes with human multipotent adipose-derived stem (hMADS) cells as a model of adult stem cells. We found that heterologous cell fusion promoted cardiomyocyte reprogramming back to a progenitor-like state. The resulting hybrid cells expressed early cardiac commitment and proliferation markers such as GATA-4, myocyte enhancer factor 2C, Nkx2.5, and Ki67 and exhibited a mouse genotype. Interestingly, human bone marrow-derived stem cells shared similar reprogramming properties than hMADS cells but not human fibroblasts, which suggests that these features might be common to multipotent cells. Furthermore, cardiac hybrid cells were preferentially generated by partial rather than permanent cell fusion and that intercellular structures composed of f-actin and microtubule filaments were involved in the process. Finally, we showed that stem cell mitochondria were transferred into cardiomyocytes, persisted in hybrids and were required for somatic cell reprogramming. In conclusion, by providing new insights into previously reported cell fusion processes, our data might contribute to a better understanding of stem cell-mediated regenerative mechanisms and thus, the development of more efficient stem cell-based heart therapies.
authors: INSERM U995, Créteil, France.
authors: Adrien
authors: A
authors: Acquistapace
authors: Thierry
authors: T
authors: Bru
authors: Pierre-François
authors: PF
authors: Lesault
authors: Florence
authors: F
authors: Figeac
authors: Amélie E
authors: AE
authors: Coudert
authors: Olivier
authors: O
authors: le Coz
authors: Christo
authors: C
authors: Christov
authors: Xavier
authors: X
authors: Baudin
authors: Fréderic
authors: F
authors: Auber
authors: René
authors: R
authors: Yiou
authors: Jean-Luc
authors: JL
authors: Dubois-Randé
authors: Anne-Marie
authors: AM
authors: Rodriguez
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002459:Cell Fusion; D002460:Cell Line; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction