Abstract
The heart and its cellular components are profoundly altered by missions to space and injury on Earth. Further research, however, is needed to characterize and address the molecular substrates of such changes. For this reason, neonatal and adult human cardiovascular progenitor cells (CPCs) were cultured aboard the International Space Station. Upon return to Earth, we measured changes in the expression of microRNAs and of genes related to mechanotransduction, cardiogenesis, cell cycling, DNA repair, and paracrine signaling. We additionally assessed endothelial-like tube formation, cell cycling, and migratory capacity of CPCs. Changes in microRNA expression were predicted to target extracellular matrix interactions and Hippo signaling in both neonatal and adult CPCs. Genes related to mechanotransduction (YAP1, RHOA) were downregulated, while the expression of cytoskeletal genes (VIM, NES, DES, LMNB2, LMNA), non-canonical Wnt ligands (WNT5A, WNT9A), and Wnt/calcium signaling molecules (PLCG1, PRKCA) was significantly elevated in neonatal CPCs. Increased mesendodermal gene expression along with decreased expression of mesodermal derivative markers (TNNT2, VWF, and RUNX2), reduced readiness to form endothelial-like tubes, and elevated expression of Bmp and Tbx genes, were observed in neonatal CPCs. Both neonatal and adult CPCs exhibited increased expression of DNA repair genes and paracrine factors, which was supported by enhanced migration. While spaceflight affects cytoskeletal organization and migration in neonatal and adult CPCs, only neonatal CPCs experienced increased expression of early developmental markers and an enhanced proliferative potential. Efforts to recapitulate the effects of spaceflight on Earth by regulating processes described herein may be a promising avenue for cardiac repair.
Highlights
Changes to the cardiovascular system during spaceflight have prompted molecular biologists to understand the mechanisms governing cellular adaptation to culture aboard the International Space Station (ISS)
In adult cardiovascular progenitor cells (CPCs), SMAD1 exhibited a significant increase in expression, while SMAD2 and TBX18 trended towards an increase in expression (Fig. 4a). These findings indicate that the transcripts of genes involved in early precardiac mesoderm development are upregulated by spaceflight in neonatal CPCs
We found that spaceflight exerts broad effects on the developmental status, proliferative potential, and migratory ability of CPCs, some of which occurred in an age-dependent manner
Summary
Changes to the cardiovascular system during spaceflight have prompted molecular biologists to understand the mechanisms governing cellular adaptation to culture aboard the International Space Station (ISS). In an effort to understand the relevant signaling events by which CPCs adapt to culture aboard the ISS, we performed microarray analysis to measure broad alterations to transcriptional control Among both neonatal and adult CPCs, 14 microRNAs exhibited significant alterations in levels of expression (Fig. 1e). The sinoatrial nodal markers HCN4 and SHOX2 exhibited elevated expression in neonatal CPCs and reduced expression in adult CPCs (Fig. 4h) Taken together, these findings indicate that spaceflight induces a pre-cardiac mesoderm gene expression profile in neonatal CPCs. ISS-cultured neonatal CPCs proliferate more rapidly than adult or ground-control CPCs. Given the change in developmental status of the cell, we sought to assess whether such changes would affect the proliferative potential of space-flown CPCs; cell cycling was assessed using flow cytometry. CPCs, regardless of age, demonstrate enhanced migratory capacity aboard the ISS
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