The m6A methyltransferase METTL16 negatively regulates MCP1 expression in mesenchymal stem cells during monocyte recruitment

Abstract

Mesenchymal stem cells (MSCs) possess strong immunoregulatory functions, one aspect of which is recruiting monocytes from peripheral vessels to local tissue by secreting MCP1. However, the regulatory mechanisms of MCP1 secretion in MSCs are still unclear. Recently, N6-methyladenosine (m 6 A) modification was reported to be involved in the functional regulation of MSCs. In this study, we demonstrated that methyltransferase-like 16 (METTL16) negatively regulated MCP1 expression in MSCs through m 6 A modification. Specifically, the expression of METTL16 in MSCs decreased gradually and was negatively correlated with the expression of MCP1 after coculture with monocytes. Knocking down METTL16 markedly enhanced MCP1 expression and the ability to recruit monocytes. Mechanistically, knocking down METTL16 decreased MCP1 mRNA degradation, which was mediated by the m 6 A reader YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). We further revealed that YTHDF2 specifically recognized m 6 A sites on MCP1 mRNA in the CDS region and thus negatively regulated MCP1 expression. Moreover, an in vivo assay showed that MSCs transfected with METTL16 siRNA showed a stronger ability to recruit monocytes. These findings reveal a potential mechanism by which the m 6 A methylase METTL16 regulates MCP1 expression through YTHDF2-mediated mRNA degradation and suggest a potential strategy to manipulate MCP1 expression in MSCs.

Immunomodulatory effects of hydatid antigens on mesenchymal stem cells: gene expression alterations and functional consequences

“…Therefore, the downregulation of chemokine expression in MSCs induced by parasite antigens may facilitate the innate immune evasion of parasites. Additionally, certain chemokines, such as CCL2, have been implicated in regulating the recruitment of MSC-osteoprogenitor cells and protecting against apoptosis induced by the external environment ( Yao et al, 2021 ; Zhang et al, 2023 ). Thus, alterations in chemokine expression in MSCs can have multiple biological effects and are closely associated with lesion development.…”

METTL16 promotes osteosarcoma progression by downregulating VPS33B in an m6A‐dependent manner

“…METTL16, as a newly identified methyltransferase, was only reported to install m 6 A modifications on a few noncoding RNAs and pre-mRNAs in majorities of studies before 2018, such as MAT2A, U6 snRNA, and MALAT1 (Brown et al, 2016;Shima et al, 2017;Warda et al, 2017) but a subsequent study revealed that METTL16 could promote the translation of more than 4000 mRNA transcripts (Su et al, 2022) which implied that it had multiple undiscovered functions. Thereafter, multiple studies concentrated on the physiological function of METTL16 and discovered that it regulated the m 6 A modification on different mRNAs (Guo et al, 2022;Zhang et al, 2022Zhang et al, , 2023.…”

Exploration of altered miRNA expression and function in MSC-derived extracellular vesicles in response to hydatid antigen stimulation

“…Previous studies have demonstrated that MSCs can induce changes in chemokine expression and osteogenic activity in themselves and surrounding cells through EVs ( Dabrowska et al, 2021 ). Chemokine expression plays a crucial role in parasite immunity by recruiting multiple immune cells and is one of the main immunomodulatory mechanisms of MSCs ( Yao et al, 2021 ; Zhang et al, 2023 ). Furthermore, in vivo experiments have revealed that transplantation of MSCs can improve the prognosis of hydatid disease by mitigating tissue damage and modulating the immune response, underscoring the significance of MSCs in the parasite–host interaction ( Kian et al, 2022 ).…”