Abstract
Direct reprogramming of somatic cells has been demonstrated, however, it is unknown whether electrophysiologically-active somatic cells derived from separate germ layers can be interconverted. We demonstrate that partial direct reprogramming of mesoderm-derived cardiomyocytes into neurons is feasible, generating cells exhibiting structural and electrophysiological properties of both cardiomyocytes and neurons. Human and mouse pluripotent stem cell-derived CMs (PSC-CMs) were transduced with the neurogenic transcription factors Brn2, Ascl1, Myt1l and NeuroD. We found that CMs adopted neuronal morphologies as early as day 3 post-transduction while still retaining a CM gene expression profile. At week 1 post-transduction, we found that reprogrammed CMs expressed neuronal markers such as Tuj1, Map2, and NCAM. At week 3 post-transduction, mature neuronal markers such as vGlut and synapsin were observed. With single-cell qPCR, we temporally examined CM gene expression and observed increased expression of neuronal markers Dcx, Map2, and Tubb3. Patch-clamp analysis confirmed the neuron-like electrophysiological profile of reprogrammed CMs. This study demonstrates that PSC-CMs are amenable to partial neuronal conversion, yielding a population of cells exhibiting features of both neurons and CMs.
Highlights
The use of direct reprogramming, or transcription factor overexpression to acquire an alternative cell fate, comprises a burgeoning area of study in regenerative medicine
As a proof-of-principle, we examined the ability of recently described neurogenic reprogramming factors Brn[2], Ascl[1], Myt1l (BAM), plus NeuroD (BAMN) to convert mouse and human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) into induced neurons[2]
Using lentiviruses that overexpress neurogenic transcription factors previously shown to induce neuronal conversion from fibroblasts, we found that mouse and human PSC-CMs are amenable to partial neuronal phenotype conversion
Summary
The use of direct reprogramming, or transcription factor overexpression to acquire an alternative cell fate, comprises a burgeoning area of study in regenerative medicine. The mesoderm-derived cardiac cell types and ectoderm-derived neurons arise from separate developmental origins, specialized cardiomyocytes of the cardiac electrical conduction network, such as Purkinje fibers, overlap with neurons in terms of gene expression for calcium and potassium channels needed for action potential propagation, intermediate filaments for the maintenance of spiny structure, and neural crest-associated markers[18,19,20]. These similarities may facilitate the reprogramming process between the two electrophysiologically active cell types. We identified partially reprogrammed, neuron-cardiomyocyte cells that harbor both cardiomyocyte and neuronal gene expression
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