N6-Methyladenosine Modification of lncCCKAR-5 Regulates Autophagy in Human Umbilical Cord Mesenchymal Stem Cells by Destabilizing LMNA and Inhibits Diabetic Wound Healing

J Invest Dermatol. 2024 May;144(5):1148-1160.e15. doi: 10.1016/j.jid.2023.11.023. Epub 2024 Jan 17.

Abstract

Long noncoding RNAs are pivotal contributors to the development of human diseases. However, their significance in the context of diabetic wound healing regulated by human umbilical cord mesenchymal stem cells (hUCMSCs) remains unclear. This study sheds light on the involvement of lncCCKAR5 in this process. We found that hUCMSCs exposed to high glucose conditions exhibited a significant downregulation of lncCCKAR5 expression, and lncCCKAR5 played a critical role in modulating autophagy, thus inhibiting apoptosis in hUCMSCs. In addition, the reduction of lncCCKAR5 in cells exposed to high glucose effectively thwarted cellular senescence and facilitated filopodium formation. Mechanistically, lncCCKAR5 served as a scaffold that facilitated the interaction between MKRN2 and LMNA, a key regulator of cytoskeletal function and autophagy. The lncCCKAR5/LMNA/MKRN2 complex played a pivotal role in promoting the ubiquitin-mediated degradation of LMNA, with this effect being further augmented by N6-adenosine methylation of lncCCKAR5. Consequently, our findings underscore the critical role of lncCCKAR5 in regulating the autophagic process in hUCMSCs, particularly through protein ubiquitination and degradation. This intricate regulatory network presents a promising avenue for potential therapeutic interventions in the context of diabetic wound healing involving hUCMSCs.

Keywords: Cell senescence; Diabetic wound; Filopodia; Human umbilical cord mesenchymal stem cells (hUCMSCs); Ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine* / analogs & derivatives*
  • Adenosine* / metabolism
  • Animals
  • Apoptosis / drug effects
  • Autophagy* / drug effects
  • Cells, Cultured
  • Cellular Senescence / drug effects
  • Glucose / metabolism
  • Glucose / pharmacology
  • Humans
  • Lamin Type A* / genetics
  • Lamin Type A* / metabolism
  • Mesenchymal Stem Cells* / drug effects
  • Mesenchymal Stem Cells* / metabolism
  • Mice
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • Umbilical Cord* / cytology
  • Wound Healing* / drug effects

Substances

  • Adenosine
  • RNA, Long Noncoding
  • N-methyladenosine
  • Lamin Type A
  • LMNA protein, human
  • Glucose