scholarly journals HSPB7 regulates osteogenic differentiation of human adipose derived stem cells via ERK signaling pathway

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Chanyuan Jin ◽  
Ting Shuai ◽  
Zhihui Tang
Keyword(s):  
Stem Cells ◽  
Heat Shock ◽  
Protein Kinase ◽  
Heat Shock Protein ◽  
Osteogenic Differentiation ◽  
Signaling Pathway ◽  
Erk Signaling ◽  
Adipose Derived Stem Cells ◽  
Extracellular Signal

Abstract Background Heat shock protein B7 (HSPB7), which belongs to small heat shock protein family, has been reported to be involved in diverse biological processes and diseases. However, whether HSPB7 regulates osteogenic differentiation of human adipose derived stem cells (hASCs) remains unexplored. Methods The expression level of HSPB7 during the osteogenesis of hASCs was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analysis. Lentivirus transfection was used to knock down or overexpress HSPB7, which enabled us to investigate the effect of HSPB7 on osteogenic differentiation of hASCs. U0126 and extracellular signal-regulated protein kinase 1/2 (ERK1/2) siRNA were used to identify the mechanism of the HSPB7/ERK1/2 axis in regulating osteogenic differentiation of hASCs. Moreover, ectopic bone formation in nude mice and osteoporosis mice model was used to investigate the effect of HSPB7 on osteogenesis in vivo. Results In this study, we found the expression of HSPB7 was significantly downregulated during the osteogenic differentiation of hASCs. HSPB7 knockdown remarkably promoted osteogenic differentiation of hASCs, while HSPB7 overexpression suppressed osteogenic differentiation of hASCs both in vitro and in vivo. Moreover, we discovered that the enhancing effect of HSPB7 knockdown on osteogenic differentiation was related to the activation of extracellular signal-regulated protein kinase (ERK) signaling pathway. Inhibition of ERK signaling pathway with U0126 or silencing ERK1/2 effectively blocked the stimulation of osteogenic differentiation induced by HSPB7 knockdown. Additionally, we found that HSPB7 expression was markedly increased in mouse bone marrow mesenchymal stem cells (mBMSCs) from the osteoporotic mice which suggested that HSPB7 might be utilized as a potential target in the development of effective therapeutic strategies to treat osteoporosis and other bone diseases. Conclusion Taken together, these findings uncover a previously unrecognized function of HSPB7 in regulating osteogenic differentiation of hASCs, partly via the ERK signaling pathway.

scholarly journals Low-intensity pulsed ultrasound stimulation facilitates in vitro osteogenic differentiation of human adipose-derived stem cells via up-regulation of heat shock protein (HSP)70, HSP90, and bone morphogenetic protein (BMP) signaling pathway

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Zhonglei Zhang ◽  
Yalin Ma ◽  
Shaowen Guo ◽  
Yi He ◽  
Gang Bai ◽  
...  
Keyword(s):  
Stem Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Osteogenic Differentiation ◽  
Bmp Signaling ◽  
Adipose Derived Stem Cells ◽  
Pulsed Ultrasound ◽  
Low Intensity Pulsed Ultrasound ◽  
Low Intensity ◽  
Morphogenetic Protein

Low-intensity pulsed ultrasound (LIPUS) has positive effects on osteogenic differentiation. However, the effect of LIPUS on osteogenic differentiation of human adipose-derived stem cells (hASCs) is unclear. In the present study, we investigated whether LIPUS could promote the proliferation and osteogenic differentiation of hASCs. hASCs were isolated and osteogenically induced with LIPUS stimulation at 20 and 30 mW cm−2 for 30 min day−1. Cell proliferation and osteogenic differentiation potential of hASCs were respectively analyzed by cell counting kit-8 assay, Alizarin Red S staining, real-time polymerase chain reaction, and Western blotting. The results indicated that LIPUS stimulation did not significantly affect the proliferation of hASCs, but significantly increased their alkaline phosphatase activity on day 6 of culture and markedly promoted the formation of mineralized nodules on day 21 of culture. The mRNA expression levels of runt-related transcription factor, osteopontin, and osteocalcin were significantly up-regulated by LIPUS stimulation. LIPUS stimulation did not affect the expression of heat shock protein (HSP) 27, HSP40, bone morphogenetic protein (BMP)-6 and BMP-9, but significantly up-regulated the protein levels of HSP70, HSP90, BMP-2, and BMP-7 in the hASCs. Further studies found that LIPUS increased the mRNA levels of Smad 1 and Smad 5, elevated the phosphorylation of Smad 1/5, and suppressed the expression of BMP antagonist Noggin. These findings indicated that LIPUS stimulation enhanced osteogenic differentiation of hASCs possibly through the up-regulation of HSP70 and HSP90 expression and activation of BMP signaling pathway. Therefore, LIPUS might have the potential to promote the repair of bone defect.

scholarly journals A Brain Penetrating Heat-Shock Protein 90 Inhibitor NXD30001 Inhibits Glioblastoma as a Monotherapy or in Combination With Radiation

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Hao Chen ◽  
Jialiang Wang ◽  
Hengli Tian
Keyword(s):  
Stem Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Median Survival ◽  
Therapeutic Potential ◽  
Heat Shock Protein 90 ◽  
Tumor Bearing ◽  
Client Proteins

Abstract INTRODUCTION It has been increasingly recognized that glioblastoma multiforme (GBM) is a highly heterogeneous disease, which is initiated and sustained by molecular alterations in an array of signal transduction pathways. Heat-shock protein 90 (Hsp90) is a molecular chaperone to be critically implicated in folding and activation of a diverse group of client proteins, many of which are key regulators of important glioblastoma biology. METHODS To determine the therapeutic potential of targeting Hsp90 in glioblastoma, we assessed the anti-neoplastic efficacy of NXD30001, a brain-penetrating Hsp90 inhibitor as a monotherapy or in combination with radiation, both in Vitro and in Vivo. RESULTS Our results demonstrated that NXD30001 potently inhibited neurosphere formation, growth and survival of CD133 + glioblastoma stem cells (GSCs) with the half maximal inhibitory concentrations (IC50) at low nanomolar concentrations. At suboptimal concentrations, inhibition of Hsp90 did not exert cytotoxic activity but rather increased radiosensitivity in GSCs. CD133- GBM cells were less sensitive and not radiosensitized by NXD30001. In lines with its cytotoxic and radiosensitizing effects, NXD30001 dose-dependently decreased phosphorylation protein levels of multiple Hsp90 client proteins, including those playing key roles in GSCs, such as EGFR, Akt, c-Myc, and Notch1. In addition, combining NXD30001 with radiation could impair DNA damage response and ER stress response to induce apoptosis of GSCs. Treatment of orthotopic glioblastoma tumors with NXD30001 extended median survival of tumor-bearing mice by approximately 20% (treated 37 days vs vehicle 31 d, P = .0026). Radiation alone increased median survival of tumor-bearing mice from 31 to 38 d, combination with NXD30001 further extended survival to 43 d (P = .0089). CONCLUSION Our results suggest that GBM stem cells (CD133+) are more sensitive to NXD30001 than non-stem GBM cells (CD133-). Furthermore, combination NXD30001 with radiation significantly inhibits GBM progression than use it as a monotherapy by targeting GSCs.

scholarly journals The Molecular Chaperone Heat Shock Protein 70 Controls Liver Cancer Initiation and Progression by Regulating Adaptive DNA Damage and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling Pathways

2019 ◽  
Vol 39 (9) ◽  
Author(s):  
Wonkyoung Cho ◽  
Xiongjie Jin ◽  
Junfeng Pang ◽  
Yan Wang ◽  
Nahid F. Mivechi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Heat Shock ◽  
Protein Kinase ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
Cell Transformation ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Delineating the mechanisms that drive hepatic injury and hepatocellular carcinoma (HCC) progression is critical for development of novel treatments for recurrent and advanced HCC but also for the development of diagnostic and preventive strategies. Heat shock protein 70 (HSP70) acts in concert with several cochaperones and nucleotide exchange factors and plays an essential role in protein quality control that increases survival by protecting cells against environmental stressors. Specifically, the HSP70-mediated response has been implicated in the pathogenesis of cancer, but the specific mechanisms by which HSP70 may support malignant cell transformation remains to be fully elucidated. Here, we show that genetic ablation of HSP70 markedly impairs HCC initiation and progression by distinct but overlapping pathways. This includes the potentiation of the carcinogen-induced DNA damage response, at the tumor initiation stage, to increase the p53-dependent surveillance response leading to the cell cycle exit or death of genomically damaged differentiated pericentral hepatocytes, and this may also prevent their conversion into more proliferating HCC progenitor cells. Subsequently, activation of a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) negative feedback pathway diminishes oncogenic signals, thereby attenuating premalignant cell transformation and tumor progression. Modulation of HSP70 function may be a strategy for interfering with oncogenic signals driving liver cell transformation and tumor progression, thus providing an opportunity for human cancer control.

scholarly journals PACAP-derived peptide MPAPO impacts Adipose-derived stem cells adipogenic differentiation

2020 ◽  
Author(s):  
Wang Zi Xian ◽  
Liu Qian ◽  
Liu Jian Min ◽  
Zheng Zi Qiong ◽  
Feng Jia ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathway ◽  
Adipogenic Differentiation ◽  
Value Added ◽  
Erk Signaling ◽  
Easy Access ◽  
High Plasticity ◽  
Adipose Derived Stem Cells ◽  
Seed Cells ◽  
Tissue Defects

Abstract BackgroundRegenerative medicine and tissue engineering have brought new therapeutic prospects to the treatment of soft tissue defects, but the selection of seed cells is the key to treatment. Adipose-derived stem cells (ASCs) have always been a popular candidate for seed cells because of their rich sources, easy access, high plasticity, and strong value-added capabilities. The purpose of the current study is to explore the role of PACAP -derived peptide MPAPO on the adipogenic differentiation of ASCs and its molecular mechanism.MethodsThe effect of MPAPO on the proliferation of adipose-derived stem cells were detected by CCK-8 assay and PI single-staining-flow. To reveal the direct effect of MPAPO on the adipogenic differentiation of ASCs, a model of adipogenic differentiation of adipose stem cells was established. In addition, adipogenic differentiation capacity was assessed using Oil-Red-O Staining, Triglyceride (TG) assay and quantification of gene expression. Finally, the relationship between ASCs adipogenic differentiation and the ERK signaling pathway was explored by Western blot.ResultsMPAPO treatment can significantly promote the proliferation of ASCs. In addition, PACAP treatment improves the adipogenic differentiation efficiency of ASCs, including promoting the accumulation of lipid droplets and triglycerides, and the expression of adipogenic-related transcription factors PPARγ and C/EBPα. The mechanism studies showed that MPAPO selectively binds to the PAC1 receptor to promote the adipogenic differentiation of ASCs via activating the ERK signaling pathway.ConclusionsThe present study shows that MPAPO could promote the adipogenic differentiation of ASCs by activating the ERK signaling pathway, and provide relevant experimental evidence for the filling of clinical tissue defects.

Sign in / Sign up

Export Citation Format

Share Document