# CISAT, a CoPP-Induced lncRNA, Improves Cardiac Mesenchymal Progenitor Cell Survival and Myocardial Repair via SFPQ/NRF2/p38 Redox Regulation

## TL;DR

A new long non-coding RNA called CISAT helps heart progenitor cells survive better and repair heart tissue by regulating redox balance and aging pathways.

## Contribution

CISAT is a novel lncRNA that improves hMPC survival and myocardial repair via SFPQ/NRF2/p38 redox regulation.

## Key findings

- CISAT overexpression reduces senescence markers and enhances hMPC survival and migration.
- CISAT-overexpressed hMPCs improve heart function and reduce fibrosis in a murine model of myocardial infarction.
- CISAT interacts with SFPQ to regulate NRF2 and inhibit p38 MAPK phosphorylation, mitigating cellular senescence.

## Abstract

Cellular therapy using human cardiac mesenchymal progenitor cells (hMPCs) for regenerative medicine is hindered by poor cell survival and senescence. Long non-coding RNAs (lncRNAs) are critical regulators of cellular processes, yet their role in cardiac aging remains underexplored. Here, lncRNA microarray profiling identified a novel lncRNA, XLOC_002543, upregulated in hMPCs preconditioned with cobalt protoporphyrin (CoPP), which was named CoPP-Induced and SFPQ-Associated RNA Transcript (CISAT) due to its interaction with splicing factor proline and glutamine rich (SFPQ), confirmed via RNA pull-down and immunoprecipitation. CISAT was the only highly expressed transcript among seven lnc-ANKMY1-5 variants in hMPCs, as shown by RT-PCR. Notably, CISAT expression decreased in aging/senescent hMPCs, correlating with elevated p16INK4A, a senescence marker. Overexpression of CISAT reduced p16INK4A levels; enhanced hMPC survival, proliferation, and migration; and increased antioxidant and anti-apoptotic protein expression, while CISAT knockdown reduced resistance to H2O2-induced oxidative stress. In vivo, intramyocardial transplantation of CISAT-overexpressed hMPCs in an immune-deficient murine myocardial infarction model reduced fibrosis, promoted angiogenesis, and preserved cardiac function. Mechanistically, CISAT interacts with SFPQ to regulate NRF2-mediated redox homeostasis and inhibits p38 MAPK phosphorylation, mitigating senescence and enhancing cell survival. These findings suggest that targeting CISAT to modulate redox signaling and p38 MAPK pathways in aging hMPCs could improve their therapeutic efficacy for myocardial repair in heart disease.