Dataset Information

Alcohol inhibits osteopontin-dependent transforming growth factor-β1 expression in human mesenchymal stem cells.

ABSTRACT: Alcohol (EtOH) intoxication is a risk factor for increased morbidity and mortality with traumatic injuries, in part through inhibition of bone fracture healing. Animal models have shown that EtOH decreases fracture callus volume, diameter, and biomechanical strength. Transforming growth factor β1 (TGF-β1) and osteopontin (OPN) play important roles in bone remodeling and fracture healing. Mesenchymal stem cells (MSC) reside in bone and are recruited to fracture sites for the healing process. Resident MSC are critical for fracture healing and function as a source of TGF-β1 induced by local OPN, which acts through the transcription factor myeloid zinc finger 1 (MZF1). The molecular mechanisms responsible for the effect of EtOH on fracture healing are still incompletely understood, and this study investigated the role of EtOH in affecting OPN-dependent TGF-β1 expression in MSC. We have demonstrated that EtOH inhibits OPN-induced TGF-β1 protein expression, decreases MZF1-dependent TGF-β1 transcription and MZF1 transcription, and blocks OPN-induced MZF1 phosphorylation. We also found that PKA signaling enhances OPN-induced TGF-β1 expression. Last, we showed that EtOH exposure reduces the TGF-β1 protein levels in mouse fracture callus. We conclude that EtOH acts in a novel mechanism by interfering directly with the OPN-MZF1-TGF-β1 signaling pathway in MSC.

SUBMITTER: Driver J

PROVIDER: S-EPMC4400371 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Alcohol inhibits osteopontin-dependent transforming growth factor-β1 expression in human mesenchymal stem cells.

Driver Joseph J Weber Cynthia E CE Callaci John J JJ Kothari Anai N AN Zapf Matthew A MA Roper Philip M PM Borys Dariusz D Franzen Carrie A CA Gupta Gopal N GN Wai Philip Y PY Zhang Jiwang J Denning Mitchell F MF Kuo Paul C PC Mi Zhiyong Z

The Journal of biological chemistry 20150224 16

Alcohol (EtOH) intoxication is a risk factor for increased morbidity and mortality with traumatic injuries, in part through inhibition of bone fracture healing. Animal models have shown that EtOH decreases fracture callus volume, diameter, and biomechanical strength. Transforming growth factor β1 (TGF-β1) and osteopontin (OPN) play important roles in bone remodeling and fracture healing. Mesenchymal stem cells (MSC) reside in bone and are recruited to fracture sites for the healing process. Resi ...[more]

PMID: 25713073

Similar Datasets

Project description:: Mesenchymal stem cells (MSCs) have been extensively investigated as a promising approach to treat many autoimmune and inflammatory diseases. The stress condition would affect the therapeutic efficacy and induce autophagy of MSCs. However, whether autophagy would affect the immunosuppressive capacity of MSCs is largely unknown. The present study aimed to assess whether autophagy plays an important role in regulating the immunomodulation of MSCs and the undermechanisms. We successfully inhibited and induced autophagy of MSCs using 3-methyladenine (3-MA) and rapamycin, respectively. Our results demonstrated that rapamycin strengthened the capacity of MSCs to inhibit CD4+ T-cell proliferation, whereas 3-MA weakened the inhibitory ability of MSCs. Mechanistically, 3-MA-pretreated MSCs secreted less, whereas rapamycin-pretreated MSCs secreted more transforming growth factor-β1 (TGF-β1) compared with the control cells. Furthermore, exogenous TGF-β1 addition recovered the immunosuppressive capacity of 3-MA-pretreated MSCs, whereas exogenous anti-TGF-β1 antibody addition reduced the immunosuppressive capacity of rapamycin-pretreated MSCs. These results indicated that the autophagy level regulates the immunosuppression of CD4+ T cells by MSCs through affecting TGF-β1 secretion and provides a novel method for improving the therapeutic efficacy of MSCs by activating autophagy.SignificanceMesenchymal stem cell (MSC)-based therapy is a promising tool to treat many diseases. Autophagy occurred in MSCs during their application, especially in those exposed to stress conditions. However, whether autophagy will affect the therapeutic efficacy of MSCs is largely unknown. This study makes a significant contribution to demonstrate that autophagy could improve the immunosuppression of CD4+ T cells by mesenchymal stem cells through transforming growth factor-β1. Therefore, regulation of autophagy in MSCs would provide a promising strategy to improve the therapeutic efficacy of these cells.

Project description:Mesenchymal stem cells (MSCs) hold great promise for vascular smooth muscle regeneration. However, most studies have mainly relied on extended supplementation of sophisticated biochemical regimen to drive MSC differentiation towards vascular smooth muscle cells (vSMCs). Herein we demonstrate a concomitant method that exploits the advantages of biomimetic matrix stiffness and tethered transforming growth factor β1 (TGF-β1) to guide vSMC commitment from human MSCs. Our designed poly(ethylene glycol) hydrogels, presenting a biomimetic stiffness and tethered TGF-β1, provide an instructive environment to potently upregulate smooth muscle marker expression in vitro and in vivo. Importantly, it significantly enhances the functional contractility of vSMCs derived from MSCs within 3 days. Interestingly, compared to non-tethered one, tethered TGF-β1 enhanced the potency of vSMC commitment on hydrogels. We provide compelling evidence that combining stiffness and tethered TGF-β1 on poly(ethylene glycol) hydrogels can be a promising approach to drastically enhance maturation and function of vSMCs from stem cell differentiation in vitro and in vivo. STATEMENT OF SIGNIFICANCE: A fast, reliable and safe regeneration of vascular smooth muscle cells (vSMCs) from stem cell differentiation is promising for vascular tissue engineering and regenerative medicine applications, but remains challenging. Herein, a photo-click hydrogel platform is devised to recapitulate the stiffness of vascular tissue and appropriate presentation of transforming growth factor β1 (TGF-β1) to guide vSMC commitment from mesenchymal stem cells (MSCs). We demonstrate that such concomitant method drastically enhanced regeneration of mature, functional vSMCs from MSCs in vitro and in vivo within only a 3-days span. This work is not only of fundamental scientific importance, revealing how physiochemical factors and the manner of their presentation direct stem cell differentiation, but also attacks the long-standing difficulty in regenerating highly functional vSMCs within a short period.

Dataset Information

Alcohol inhibits osteopontin-dependent transforming growth factor-β1 expression in human mesenchymal stem cells.

Publications

Alcohol inhibits osteopontin-dependent transforming growth factor-β1 expression in human mesenchymal stem cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets