Cardiac Differentiation Is Driven by NKX2.5 and GATA4 Nuclear Translocation in Tissue-Specific Mesenchymal Stem Cells

Abstract

Myocardial infarction is a major public health problem that causes significant mortality despite recent advances in its prevention and treatment. Therefore, approaches based on adult stem cells represent a promising alternative to conventional therapies for this life-threatening condition. Mesenchymal stem cells (MSCs) are self-renewing pluripotent cells that have been isolated from multiple tissues and differentiate to various cell types. Here we have analyzed the capacity of MSCs from human bone marrow (BMSC), adipose tissue (ATSC), and dental pulp (DPSC) to differentiate to cells with a cardiac phenotype. Differentiation of MSCs was induced by long-term co-culture with neonatal rat cardiomyocytes (CMs). Shortly after the establishment of MSC-CM co-cultures, expression of connexin 43 and the cardiac-specific markers troponin I, beta-myosin heavy chain, atrial natriuretic peptide, and alpha-sarcomeric actinin was detected in BMSCs, ATSCs, and DPSCs. Expression of differentiation markers increased over time in the co-cultures, reaching the highest levels at 4 weeks. Translocation of the transcription factors NKX2.5 and GATA4 to the nucleus was observed in all three cultures of MSCs during the differentiation process; moreover, nuclear localization of NKX2.5 and GATA4 correlated with expression of alpha-sarcomeric actinin. These changes were accompanied by an increase in myofibril organization in the resulting CM-like cells as analyzed by electron microscopy. Thus, our results provide novel information regarding the differentiation of tissue-specific MSCs to cardiomyocytes and support the potential use of MSCs in cell-based cardiac therapies.

Isolation, Characterization and Differentiation Potential of Cardiac Progenitor Cells in Adult Pigs

“…Although PACPs share some molecular and functional properties with MSCs, they also express genes representative of early and late cardiac transcription factors, such as Gata6 (Koutsourakis et al 1999), Mef2a (Potthoff et al 2007), Nkx2.5 (Arminan et al 2009;Arminan et al 2010) and ANP (Guan et al 1999;Miller-Hance et al 1993), respectively ( Figure 28, Table 7), indicating that they are part of a progenitor population addressed to the formation of the cardiac mesoderm (Rajala et al 2011). This gene expression pattern is possibly involved in conferring PACPs the ability to respond to specific stimuli and further differentiate along the cardiac lineage.…”

Neural Crest Stem Cells Can Differentiate to a Cardiomyogenic Lineage with an Ability to Contract in Response to Pulsed Infrared Stimulation

“…37 Additionally, NKX2.5 is known to interact with GATA4, which although not statistically significant, we do see a small upregulation of. 14,37 The smaller than expected increase is not surprising as cells of the migrating neural crest origin are known to also express GATA4. 38 This is also true of MEF2C; however, the translocation into the nucleus may show activation of the transcription factor.…”

“…12 Dental tissue is known to harbor a population of stem cells, which are reportedly mainly mesenchymal in nature. 13 Additionally, in vitro differentiation to cardiomyogenic lineages 14 and perfusion studies on small animal models following MI using stem cells derived from dental tissue have been carried out. 15 One tissue in which potential stem cells may be found is from periodontal ligament (PDL).…”

Cardiac Stem Cells Differentiate into Sinus Node-Like Cells

“…The cells could proliferate by clonal expansion and differentiate spontaneously into cardiomyocytes in vitro but fail to contract automatically. The cardiac transcription factor GATA-4, which is essential for normal heart morphogenesis and regulates the survival, growth and proliferation of cardiomyocytes (Armiñán et al 2009;Zaglia et al 2009;Singh et al 2010), could be considered as early marker of differentiated cardiomyocyte. Hyperpolarization-activated nucleotide-gated (HCN) channel family genes, which figure prominently in physiological automaticity, are related to automatic pacing activity.…”