Mesenchymal stem cells (MSCs) show unexplained differences in differentiation potential. In this study, differentiation of human (h) MSCs derived from embryonic, fetal and adult sources toward cardiomyocytes, endothelial and smooth muscle cells was investigated. Labeled hMSCs derived from embryonic stem cells (hESC-MSCs), fetal umbilical cord, bone marrow, amniotic membrane and adult bone marrow and adipose tissue were co-cultured with neonatal rat cardiomyocytes (nrCMCs) or cardiac fibroblasts (nrCFBs) for 10 days, and also cultured under angiogenic conditions. Cardiomyogenesis was assessed by human-specific immunocytological analysis, whole-cell current-clamp recordings, human-specific qRT-PCR and optical mapping. After co-culture with nrCMCs, significantly more hESC-MSCs than fetal hMSCs stained positive for α-actinin, whereas adult hMSCs stained negative. Furthermore, functional cardiomyogenic differentiation, based on action potential recordings, was shown to occur, but not in adult hMSCs. Of all sources, hESC-MSCs expressed most cardiac-specific genes. hESC-MSCs and fetal hMSCs contained significantly higher basal levels of connexin43 than adult hMSCs and co-culture with nrCMCs increased expression. After co-culture with nrCFBs, hESC-MSCs and fetal hMSCs did not express α-actinin and connexin43 expression was decreased. Conduction velocity (CV) in co-cultures of nrCMCs and hESC-MSCs was significantly higher than in co-cultures with fetal or adult hMSCs. In angiogenesis bioassays, only hESC-MSCs and fetal hMSCs were able to form capillary-like structures, which stained for smooth muscle and endothelial cell markers.Human embryonic and fetal MSCs differentiate toward three different cardiac lineages, in contrast to adult MSCs. Cardiomyogenesis is determined by stimuli from the cellular microenvironment, where connexin43 may play an important role.
Lloyd-Jones D, Adams R, Carnethon M, De SG, Ferguson TB, et al. (2009) Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119: 480–486.
Semenov OV, Koestenbauer S, Riegel M, Zech N, Zimmermann R, et al. (2010) Multipotent mesenchymal stem cells from human placenta: critical parameters for isolation and maintenance of stemness after isolation. Am J Obstet Gynecol 202: 193.
Jo CH, Kim OS, Park EY, Kim BJ, Lee JH, et al. (2008) Fetal mesenchymal stem cells derived from human umbilical cord sustain primitive characteristics during extensive expansion. Cell Tissue Res 334: 423–433.
Nishiyama N, Miyoshi S, Hida N, Uyama T, Okamoto K, et al. (2007) The significant cardiomyogenic potential of human umbilical cord blood-derived mesenchymal stem cells in vitro. Stem Cells 25: 2017–2024.
Pijnappels DA, Schalij MJ, Ramkisoensing AA, van Tuyn J, de Vries AA, et al. (2008) Forced alignment of mesenchymal stem cells undergoing cardiomyogenic differentiation affects functional integration with cardiomyocyte cultures. Circ Res 103: 167–176.
Hwang NS, Varghese S, Lee HJ, Zhang Z, Ye Z, et al. (2008) In vivo commitment and functional tissue regeneration using human embryonic stem cell-derived mesenchymal cells. Proc Natl Acad Sci U S A 105: 20641–20646.
In 't Anker PS, Scherjon SA, Kleijburg-van der KC, de Groot-Swings GM, Claas FH, et al. (2004) Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells 22: 1338–1345.
Roubelakis MG, Pappa KI, Bitsika V, Zagoura D, Vlahou A, et al. (2007) Molecular and proteomic characterization of human mesenchymal stem cells derived from amniotic fluid: comparison to bone marrow mesenchymal stem cells. Stem Cells Dev 16: 931–952.
Chen MY, Lie PC, Li ZL, Wei X (2009) Endothelial differentiation of Wharton's jelly-derived mesenchymal stem cells in comparison with bone marrow-derived mesenchymal stem cells. Exp Hematol 37: 629–640.
Pijnappels DA, Schalij MJ, van Tuyn J, Ypey DL, de Vries AA, et al. (2006) Progressive increase in conduction velocity across human mesenchymal stem cells is mediated by enhanced electrical coupling. Cardiovasc Res 72: 282–291.
Liechty KW, MacKenzie TC, Shaaban AF, Radu A, Moseley AM, et al. (2000) Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 6: 1282–1286.
Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, et al. (2009) A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 54: 2277–2286.