Simulated microgravity impairs cardiac autonomic neurogenesis from neural crest cells.

Simulated microgravity impairs cardiac autonomic neurogenesis from neural crest cells.

Stem Cells Dev. 2018 Jan 16;:

Authors: Hatzistergos KE, Jiang Z, Valasaki K, Takeuchi LM, Balkan W, Atluri P, Saur D, Seidler B, Tsinoremas N, DiFede D, Hare JM

Abstract Microgravity-induced alterations in the autonomic nervous system (ANS) contribute to derangements in both the mechanical and electrophysiologic function of the cardiovascular system, leading to severe symptoms in humans following space travel. Because the ANS forms embryonically from neural crest progenitors (NCs), we hypothesized that microgravity can impair NC derived cardiac structures. Accordingly, we conducted in vitro simulated microgravity experiments employing NC genetic lineage-tracing in mice with cKitCreERT2/+, Isl1nLacZ and Wnt1-Cre reporter alleles. Inducible fate-mapping in adult mouse hearts and pluripotent stem cells (iPSCs) demonstrated reduced cKitCreERT2/+-mediated labeling of both NC-derived cardiomyocytes and autonomic neurons (p<0.0005 vs. controls). Whole-transcriptome analysis, suggested that this effect was associated with repressed cardiac NC- and upregulated mesoderm-related gene-expression profiles, coupled with abnormal BMP/TGF-β and Wnt/β-catenin signaling. To separate the manifestations of simulated microgravity on NC- vs. mesodermal-cardiac derivatives, we conducted Isl1nLacZ lineage analyses which indicated a ~3-fold expansion (p<0.05) in mesoderm-derived Isl-1+ pacemaker sinoatrial nodal cells; and a ~3-fold reduction (p<0.05) in cardiac NC-derived ANS cells, including sympathetic nerves and Isl-1+ cardiac ganglia. Finally, NC-specific fate-mapping with a Wnt1-Cre reporter iPSC model of murine NC development confirmed that simulated microgravity directly impacted the in vitro development of cardiac NC progenitors and their contribution to the sympathetic and parasympathetic innervation of the iPSC-derived myocardium. Together these findings reveal an important role for gravity in the development of NCs and their postnatal derivatives; and have important therapeutic implications for human space exploration, providing insights into cellular and molecular mechanisms of microgravity-induced cardiomyopathies/ channelopathies.

PMID: 29336212 [PubMed - as supplied by publisher]