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In Vitro Differentiation of Human Mesenchymal Stem Cells into Functional Cardiomyocyte-like Cells
Published on: August 9, 2017
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Pacemaker cell characteristics of differentiated and HCN4-transduced human mesenchymal stem cells
Fabrice F Darche1, Rasmus Rivinius1, Eva Köllensperger2
1Department of Cardiology, Medical University Hospital Heidelberg, INF 410, D-69120 Heidelberg, Germany.
Life Sciences
|July 11, 2019
Summary
Human mesenchymal stem cells (haMSC) differentiated and transduced with HCN4 show potential as biological pacemakers. This approach offers a promising alternative to electronic devices for controlling heart rate.
Area of Science:
- Regenerative Medicine & Cardiology
- Stem Cell Biology
- Biomedical Engineering
Background:
- Electronic pacemakers have limitations and side effects.
- Cell-based biological pacemakers offer a potential alternative.
- Mesenchymal stem cells (MSCs) are being investigated for cardiac applications.
Purpose of the Study:
- To develop and test nodal-type differentiation of human adipose-derived (haMSC) and bone marrow-derived (hbMSC) mesenchymal stem cells.
- To evaluate the potential of these differentiated cells as biological pacemakers.
- To investigate the role of the HCN4 channel in cellular pacemaking function.
Main Methods:
- Customized differentiation protocols for haMSC and hbMSC.
- Quantitative RT-PCR for gene expression profiling of pacemaker-related genes.
- Immunocytochemistry for protein membrane expression analysis.
- Patch clamp recordings to study pacemaker current (If) in haMSC.
- Lentiviral transduction of haMSC with HCN4.
- Co-culture experiments with neonatal rat ventricular myocytes (NRVM) to assess functional characteristics.
Main Results:
- Differentiated haMSC and hbMSC showed abundant transcription of ion channel, transcription factor, and connexin genes characteristic of cardiac pacemaker tissue, but lacked adequate HCN transcription.
- haMSC-derived cells exhibited transcriptional profiles closer to sinoatrial nodal cells compared to hbMSC-derived cells.
- Lentiviral HCN4-transduction of haMSC resulted in stable If, enabling spontaneous contractions in co-culture with NRVM.
- Differentiated haMSC expressing HCN4 demonstrated improved beating rate, regularity, synchrony, and earlier onset of contractions compared to controls.
- Increased membrane expression of cardiac gap junctional proteins was observed in differentiated haMSC.
Conclusions:
- Differentiated haMSC, not hbMSC, possess favorable properties for cardiac pacemaking.
- Lentiviral HCN4-transduction of differentiated haMSC generates a cellular phenotype capable of sustainably controlling and stabilizing heart rate.
- This study presents a promising strategy for developing cell-based biological pacemakers.
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