22‐kD growth hormone‐induced nuclear GHR/STAT5/CyclinD1 signaling pathway plays an important role in promoting mesenchymal stem cell proliferation

Abstract

Growth hormone (GH) exhibited the important biological activities in the mesenchymal stem cell (MSCs). However, the cellular behavior and properties of GH/GHR in MSCs remain unclear. A series of experiments (such as confocal laser scanning microscope [CLSM] and Western-blot) were performed to systematically investigate the cellular behavior of GH/GHR in MSCs, and the results showed that GH/GHR not only internalized into the cytoplasm, but also transported into the cell nuclei of MSCs. Furthermore, we studied the molecular mechanism by which GH/GHR internalized into cell, and the results indicated that clathrin plays more important role in the process of GHR internalization. More importantly, it can be found that nuclear-targeted GHR has the important biological functions in MSCs, which could promote MSCs proliferation. We further revealed the molecular mechanism by which nuclear-localized GHR regulates MSCs proliferation, and found that nucleartargeted GHR enhanced the phosphorylation of STAT5, and the activated STAT5 initiates the transcription of CyclinD1, after which, the complex of CyclinD1 and CDK4 further phosphorylates Rb, and the activated Rb releases E2F1, the released E2F1 ultimately realizes the biological function of GH promoting cell proliferation. In short, in the current study，we used MSCs as a model to study the cellular behavior and properties of GH/GHR, and found that GH/GHR can internalize into cell cytoplasm and transport into the cell nuclei. Further work showed that nuclear GHR could drive cell proliferation via GHR/STAT5/CyclinD1 signaling pathway. The current research has laid an important foundation for further study on the regulatory effect of GH on MSCs.

Non-pituitary GH regulation of the tissue microenvironment

“…Mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) constitute a reserve to replace damaged and aged cells (Caplan 2005, da Silva Meirelles et al 2006 and may differentiate into chondrocytes, myocytes, osteoblasts, and adipocytes (Pittenger et al 2019). Activated npGH can affect MSC proliferation by triggering GHR internalization and nuclear translocation via STAT5 phosphorylation and initiation of cyclinD1 and cyclinD1/CDK4 to phosphorylate Rb and release E2F1, which, in turn, promotes MSC proliferation (Zheng et al 2022). npGH can also suppress differentiation toward adipocytes in MSCs derived from human trabecular bone (Bolamperti et al 2019).…”

The growth hormone receptor interacts with transcriptional regulator HMGN1 upon GH-induced nuclear translocation

“…Nuclear localisation of the GHR has functional consequences such as increased proliferative status in vitro and in vivo as demonstrated in cell lines, a liver regeneration model and in transgenic zebrafish models (Conway-Campbell et al 2007 ; Figueiredo et al 2016 ; Zheng et al 2022 ). Furthermore, constitutive nuclear localisation of the GHR in murine pro-B cells resulted in metastatic tumours when injected into nude mice suggesting a role in tumorigenesis and tumour progression (Conway-Campbell et al 2007 ).…”