Phospholipase C delta 4 (PLC delta 4) is a nuclear protein involved in cell proliferation and senescence in mesenchymal stromal stem cells

摘要

Ca2+ is an important second messenger, and it is involved in many cellular processes such as cell death and proliferation. The rise in intracellular Ca2+ levels can be due to the generation of inositol 1,4,5-trisphosphate (InsP(3)), which is a product of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis by phospholipases C (PLCs), that leads to Ca2+ release from endoplasmic reticulum by InsP(3) receptors (InsP(3)R). Ca2+ signaling patterns can vary in different regions of the cell and increases in nuclear Ca2+ levels have specific biological effects that differ from those of Ca2+ increase in the cytoplasm. There are PLCs in the cytoplasm and nucleus, but little is known about the functions of nuclear PLCs. This work aimed to characterize phenotypically the human PLC delta 4 (hPLC delta 4) in mesenchymal stem cells. This nuclear isoform of PLC is present in different cell types and has a possible role in proliferative processes. In this work, hPLC delta 4 was found to be mainly nuclear in human adipose-derived mesenchymal stem cells (hASC). PLC delta 4 knockdown demonstrated that it is essential for hASC proliferation, without inducing cell death. An increase of cells in G1, and a reduction of cells on interphase and G2/M in knockdown cells were seen. Furthermore, PLC delta 4 knockdown increased the percentage of senescent cells, p1(6INK Lambda)(+) and p21(Cip1) mRNAs expression, which could explain the impaired cell proliferation. The results show that hPLC delta 4 is in involved in cellular proliferation and senescence in hASC.