Fibroblast Growth Factor 2 Regulates High Mobility Group A2 Expression in Human Bone Marrow‐Derived Mesenchymal Stem Cells

Abstract

Mesenchymal stem cells (MSCs) are an excellent source for numerous cellular therapies due to their simple isolation, low immunogenicity, multipotent differentiation potential and regenerative secretion profile. However, over-expanded MSCs show decreased therapeutic efficacy. This shortcoming may be circumvented by identifying methods that promote self-renewal of MSCs in culture. HMGA2 is a DNA-binding protein that regulates self-renewal in multiple types of stem cells through chromatin remodeling, but its impact on human bone marrow-derived MSCs is not known. Using an isolation method to obtain pure MSCs within 9 days in culture, we show that expression of HMGA2 quickly decreases during early expansion of MSCs, while let-7 microRNAs (which repress HMGA2) are simultaneously increased. Remarkably, we demonstrate that FGF-2, a growth factor commonly used to promote self-renewal in MSCs, rapidly induces HMGA2 expression in a time-and concentration-dependent manner. The signaling pathway involves FGF-2 receptor 1 (FGFR1) and ERK1/2, but acts independent from let-7. By silencing HMGA2 using shRNAs, we demonstrate that HMGA2 is necessary for MSC proliferation. However, we also show that over-expression of HMGA2 does not increase cell proliferation, but rather abrogates the mitogenic effect of FGF-2, possibly through inhibition of FGFR1. In addition, using different methods to assess in vitro differentiation, we show that modulation of HMGA2 inhibits adipogenesis, but does not affect osteogenesis of MSCs. Altogether, our results show that HMGA2 expression is associated with highly proliferating MSCs, is tightly regulated by FGF-2, and is involved in both proliferation and adipogenesis of MSCs.

MicroRNA‑98‑5p prevents bone regeneration by targeting high mobility group AT‑Hook 2

“…The effect of miR-98-5p on the osteogenic differentiation of the mouse preosteoblast cell line, MC3T3-E1, was subsequently investigated in the current study. Consistent with previous studies (27,29), the results of the present study demonstrated that miR-98-5p significantly inhibited MC3T3-E1 cell osteogenic differentiation by repressing the expression of HMGA2. In addition, miR-98-5p upregulation significantly inhibited cell viability and induced apoptosis in MC3T3-E1 cells and these effects were eliminated by HMGA2 overexpression.…”

“…HMGA2 is a nuclear-binding protein that serves an important role in the regulation of cell proliferation and differentiation (26). A previous study has demonstrated that HMGA2 knockdown results in the inhibition of MSC proliferation (27). The effect of miR-98-5p on the osteogenic differentiation of the mouse preosteoblast cell line, MC3T3-E1, was subsequently investigated in the current study.…”

“…High mobility group AT-Hook 2 (HMGA2), also known as HMGI-C, is a nuclear-binding protein, which serves a key role in the regulation of cell proliferation and differentiation (26). A previous study revealed that HMGA2 knockdown significantly inhibited the proliferation of bone marrow-derived mesenchymal stem cells (MSCs) (27). However, in recent years, the role of HMGA2 in osteoblast differentiation has been controversial.…”

Knockdown of high mobility group box 3 impairs cell viability and colony formation but increases apoptosis in A549 human non‑small cell lung cancer cells

“…Several members of the HMGB family have been found to promote self-renewal and colony formation in stem cells as well as in cancer cells (22)(23)(24)(25)(26)(27)(28), indicating the presence of an association between these two cell types; however, the detailed molecular mechanisms underlying their cancer-promoting activity remain obscure. HMGB3 belongs to the HMGB family, members of which are proposed to regulate gene transcription by affecting DNA structure and influencing transcription complex formation or by altering gene availability (29).…”

Molecular and Lifestyle Factors Modulating Obesity Disease

“…FGF2 exerts a positive effect in promoting chondrogenic differentiation when supplemented during cell expansion [17]. FGF2 inhibitory effect on adipogenesis has also been observed; this effect has been shown to involve the high mobility group A-2 (HMGA2) [18]. Additionally, FGF1 reduces the expression of BMP and activin membrane-bound inhibitor homolog (BAMBI) by affecting the PI3K pathway promoting adipogenic differentiation [19].…”