Copyright © 2005, European Society of Cardiology
Electrophysiological properties of mouse bone marrow c-kit+ cells co-cultured onto neonatal cardiac myocytes
aLaboratorio di Biologia Vascolare e Terapia Genica, Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
bLaboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Via dei Monti di Creta 104, 00167 Rome, Italy
cLaboratorio di Biofisica, Dipartimento di Fisiologia Umana e Farmacologia "V. Erspamer", Centro di Eccellenza BEMM, Università La Sapienza, Rome, Italy
* Corresponding author. Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Via dei Monti di Creta 104, 00167 Rome, Italy. Tel.: +39 6 6646 2428; fax: +39 6 6646 2430. Email address: m.pesce{at}idi.it
Objective: Controversy about hematopoietic stem cells reprogramming into cardiac myocytes is currently supported by positive and negative findings. In fact, some reports have shown the ability of stem cells from the bone marrow (BM) to differentiate into cardiac myocytes and to contribute to myocardium repair, while others have reported the opposite.
Methods: C-kit+ cells from mouse bone marrow were co-cultured onto neonatal cardiac myocytes. Hematopoietic stem cell-derived cells were analyzed by investigating the expression of cardiac markers and ion channels and by single-cell electrophysiological recordings.
Results: Groups of undifferentiated c-kit+ cells displayed only outward currents. Co-cultured c-kit+ stem cells on neonatal cardiac myocytes expressed cardiac markers and Na+ and Ca2+ voltage-gated ion channels. However, Na+ and Ca2+ currents were not detected by electrophysiological patch-clamp recordings even if caffeine and cyclopiazonic acid treatment showed the presence of intracellular calcium stores. This suggests that these channels, although expressed, were not functional and thus do not allow the coupling between excitation and contraction that is typical of cardiac myocytes. Nevertheless, co-cultured cells had a more hyperpolarized resting membrane potential and, at least in a subset of cells, displayed voltage-gated inward rectifier currents and outward currents. Co-cultured c-kit+-derived cells were not connected to surrounding cardiac myocytes through gap junctions. To induce a more pronounced differentiation, co-cultured cells were treated with BMP-4 and TGF-β, two factors that were shown to trigger a cardiac myocyte differentiation pathway in embryonic stem (ES) cells. Even under these conditions, c-kit+ cells did not differentiate into functionally active cardiac myocytes. However, TGF-β/BMP-4-treated cells were hyperpolarized and showed and increased inward rectifier current density.
Conclusions: Our study shows that mouse BM hematopoietic stem cells exhibit a limited plasticity to transdifferentiate into cardiac myocytes in culture.
KEYWORDS Cardiac myocyte; Stem cell; Reprogramming; Electrophysiology; Bone marrow; C-kit; TGF-β; BMP-4
Time for primary review 26 days
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