The protective effects of HMGA2 in the senescence process of bone marrow‐derived mesenchymal stromal cells

Abstract

Bone marrow-derived mesenchymal stromal cells (MSCs) have been wildly applied to cell-based strategies for tissue engineering and regenerative medicine; however, they have to undergo the senescence process and thus appeared to be less therapeutic effective. HMGA2, a protein belonged to high mobility group A (HMGA) family, exhibits an inverse expression level related to embryonic development and acts as a developmental regulator in stem cell self-renewal progression. Therefore, we performed senescence-associated β-galactosidase (SA-β-gal) staining, transwell assay, to examine the changes of MSCs in different stages and then over-expressed HMGA2 in MSCs by lentivirus transfection. We found the percentage of SA-β-gal staining positive cells in MSCs from 24-month-old Sprague-Dawley (SD) rats (O-MSCs) was significantly higher compared with MSCs from 2-week-old SD rats (Y-MSCs), and the expression levels of P21 and P53, two senescence-related molecules, were also significantly up-regulated in O-MSCs than in Y-MSCs. In contrast, the HMGA2 expression level in O-MSCs was dramatically down-regulated in contrast to Y-MSCs. In additional, the migration ability in O-MSCs was significantly attenuated than in Y-MSCs. After successfully over-expressed HMGA2 in O-MSCs, the percentage of SAβ-gal staining positive cells and the expression levels of P21 and P53 were reduced, and the migration ability was improved compared with O-MSCs without treatment. Further, mRNA sequencing analysis revealed that overexpression of HMGA2 changed the expression of genes related to cell proliferation and senescence, such as Lyz2, Pf4, Rgs2, and Mstn. Knockdown of Rgs2 in HMGA2 overexpression O-MSCs could antagonize the protective effect of HMGA2 in the senescence process of O-MSCs.

HMGA2 promotes resistance against paclitaxel by targeting the p53 signaling pathway in colorectal cancer cells

“…HMGA2 can physically interact with MDM2 and p53. HMGA2 decreased the protein stability of p53 in an MDM2-mediated p53 ubiquitination manner [ 31 , 33 ], which showed a good association with our data and further suggests the reliability of our results and the importance of HMGA2 in p53 regulation.…”

“…The HMGA2 protein can exert oncogenicity in several ways, such as activation of the cell cycle, enhancement of transcriptional factor activity, maintenance of self-renewing activity of stem cells, interference with apoptosis, and impairment of DNA repair, which is dependent on the downstream genes. HMGA2 can inhibit the expression of p16INK4A and p19ARF to inhibit cellular senescence and maintain stem cell properties [ 31 , 32 ]. Yu et al showed that HMGA2 improved proliferation by inducing the pI3K/AKT/mTOR/p70S6K signaling and inhibiting p21CIP1/WAF1 expression [ 32 ].…”

Integration of Transcriptome and MicroRNA Profile Analysis of iMSCs Defines Their Rejuvenated State and Conveys Them into a Novel Resource for Cell Therapy in Osteoarthritis

“…Among them, we found many genes with increased expression in iMSCs playing essential roles in embryonic tissues and development, indicating that iMSCs possess features associated with early development that could be possibly associated with enhanced regenerative properties. In that regard, a very interesting finding was that among up-regulated genes in iPSCs and iMSCs was HMGA2 , a gene coding for a chromatin architectural protein expressed at high levels in hESCs and iPSCs and being further transiently up-regulated during the very early stages of hESC/iPSC differentiation [ 67 ]. HMGA2 seems to regulate the balance between self-renewal and differentiation of stem cells [ 63 , 68 ].…”