Abstract
Different subtypes of bone marrow-derived stem cells are characterized by varying functionality and activity after transplantation into the infarcted heart. Improvement of stem cell therapeutics requires deep knowledge about the mechanisms that mediate the benefits of stem cell treatment. Here, we demonstrated that co-transplantation of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) led to enhanced synergistic effects on cardiac remodeling. While HSCs were associated with blood vessel formation, MSCs were found to possess transdifferentiation capacity. This cardiomyogenic plasticity of MSCs was strongly promoted by a gap junction-dependent crosstalk between myocytes and stem cells. The inhibition of cell-cell coupling significantly reduced the expression of the cardiac specific transcription factors NKX2.5 and GATA4. Interestingly, we observed that small non-coding RNAs are exchanged between MSCs and cardiomyocytes in a GJ-dependent manner that might contribute to the transdifferentiation process of MSCs within a cardiac environment. Our results suggest that the predominant mechanism of HSCs contribution to cardiac regeneration is based on their ability to regulate angiogenesis. In contrast, transplanted MSCs have the capability for intercellular communication with surrounding cardiomyocytes, which triggers the intrinsic program of cardiogenic lineage specification of MSCs by providing cardiomyocyte-derived cues.
Highlights
Myocardial transplantation of adult stem cells offers a promising opportunity for cardiac regeneration and re-growth of irreversibly damaged tissue following myocardial infarction (MI) the beneficial effect is mostly limited (~3–5% functional improvement) and obtained results are often inconsistent[1,2,3]
We intended to study the therapeutic capacity of CD271+ and CD133+ BM derived stem cells independently and in synergy, upon simultaneous injection
The frequency of CD271+/CD133+ cell subpopulation was analyzed in total BM and we found that 0.017 ± 0.006% expressed both CD133 and CD271 surface markers (Fig. 1a)
Summary
Myocardial transplantation of adult stem cells offers a promising opportunity for cardiac regeneration and re-growth of irreversibly damaged tissue following myocardial infarction (MI) the beneficial effect is mostly limited (~3–5% functional improvement) and obtained results are often inconsistent[1,2,3]. The difference between the underlying regenerative mechanisms of these cell types was investigated Another possible improvement strategy for stem cell therapeutics implies the enhancement of cell properties. Apart from artificially guided cellular plasticity, cardiac lineage specification of stem cells has been described to be an intrinsic event that is induced when cells are integrated into a cardiac environment[11,12,13,14] Precise knowledge about these endogenous mechanisms will help to identify novel strategies for manipulation of cells in order to enhance their cardiac differentiation potential for clinical application e.g., by activation of their intrinsic transdifferentiation program. Similar mechanisms might be involved in the regulation of the fate of transplanted cells by the host myocardium
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