Dataset Information

Nanofibers Regulate Single Bone Marrow Stem Cell Osteogenesis via FAK/RhoA/YAP1 Pathway.

ABSTRACT: Understanding cell-material interactions is a prerequisite for the development of bio-inspired materials for tissue regeneration. While nanofibrous biomaterials have been widely used in tissue regeneration, the effects of nanofibrous architecture on stem cell behaviors are largely ambiguous because the previous biomaterial systems used for nanofiber-cell interactions could not exclude the interference of cell-cell interactions. In this study, we developed a unique micropatterning technology to confine one single stem cell in a microisland of the nanofibrous micropatterned matrix; therefore, eliminating any potential intercellular communications. The nanofibrous micropatterned matrix, which mimicked both the physical architecture and chemical composition of natural extracellular matrix, was fabricated by a combination of electrospinning, chemical crosslinking, and UV-initiated photolithography. Compared to the non-nanofibrous architecture, a bone marrow mesenchymal stem cell (BMSC) cultured on the nanofibrous microisland exhibited a more in vivo-like morphology, a smaller spreading area, less focal adhesion, and fewer stress fibers. The BMSC cultured on the nanofibrous microisland also had higher alkaline phosphatase activity, indicating nanofibrous architecture promoted BMSC differentiation. A mechanistic study reveals that nanofibers regulate single BMSC osteogenesis via the FAK/RhoA/YAP1 pathway. The nanofibrous micropatterned matrix developed in this study is an excellent platform to promote the fundamental understanding of cell-matrix interactions, ultimately provide valuable insights for the development of novel bio-inspired scaffolds for tissue regeneration.

SUBMITTER: Chang B

PROVIDER: S-EPMC6436105 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Nanofibers Regulate Single Bone Marrow Stem Cell Osteogenesis via FAK/RhoA/YAP1 Pathway.

Chang Bei B Ma Chi C Liu Xiaohua X

ACS applied materials & interfaces 20180918 39

Understanding cell-material interactions is a prerequisite for the development of bio-inspired materials for tissue regeneration. While nanofibrous biomaterials have been widely used in tissue regeneration, the effects of nanofibrous architecture on stem cell behaviors are largely ambiguous because the previous biomaterial systems used for nanofiber-cell interactions could not exclude the interference of cell-cell interactions. In this study, we developed a unique micropatterning technology to c ...[more]

PMID: 30188689

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Project description:Chordin-like 1 (CHRDL1) is a secreted glycoprotein with repeated cysteine-rich domains, which can bind to BMPs family ligands. Although it has been reported to play important roles in several systems, the exact roles of CHRDL1 on human bone mesenchymal stem cells (hBMSCs) osteogenesis remain to be explored. The present study aimed to investigate the roles of CHRDL1 on the osteogenic differentiation of hBMSCs and the underlying molecular mechanisms. We found that CHRDL1 was upregulated during hBMSCs osteogenesis, and rhBMP-4 administration could enhance CHRDL1 mRNA expression in a dose and time dependent manner. Knockdown of CHRDL1 did not affect hBMSCs proliferation, but inhibited the BMP-4-dependent osteogenic differentiation, showing decreased mRNA expression levels of osteogenic markers and reduced mineralization. On the contrary, overexpression of CHRDL1 enhanced BMP-4 induced osteogenic differentiation of hBMSCs. Moreover, in vivo experiments by transplanting CHRDL1 gene modified hBMSCs into nude mice defective femur models displayed higher new bone formation in CHRDL1 overexpression groups, but lower new bone formation in CHRDL1 knockdown groups, compared with control groups. In consistent with the bone formation rate, there were increased CHRDL1 protein expression in new bone formation regions of defective femur in CHRDL1 overexpression groups, while reduced CHRDL1 protein expression in CHRDL1 knockdown groups compared with control groups. These indicate that CHRDL1 can promote osteoblast differentiation in vivo. Furthermore, the mechanisms study showed that CHRDL1 improved BMP-4 induced phosphorylation of SMAD1/5/9 during osteogenic differentiation of hBMSCs. Besides, promotion of osteogenic differentiation and the activation of SMAD phosphorylation by CHRDL1 can be blocked by BMP receptor type I inhibitor LDN-193189. In conclusion, our results suggested that CHRDL1 can promote hBMSCs osteogenic differentiation through enhancing the activation of BMP-4-SMAD1/5/9 pathway.

Project description:Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by the formation of extraskeletal bone, or heterotopic ossification (HO), in soft connective tissues such as skeletal muscle. All familial and sporadic cases with a classic clinical presentation of FOP carry a gain-of-function mutation (R206H; c.617 G > A) in ACVR1, a cell surface receptor that mediates bone morphogenetic protein (BMP) signaling. The BMP signaling pathway is recognized for its chondro/osteogenic-induction potential, and HO in FOP patients forms ectopic but qualitatively normal endochondral bone tissue through misdirected cell fate decisions by tissue-resident mesenchymal stem cells. In addition to biochemical ligand-receptor signaling, mechanical cues from the physical environment are transduced to activate intracellular signaling, a process known as mechanotransduction, and can influence cell fates. Utilizing an established mesenchymal stem cell model of mouse embryonic fibroblasts (MEFs) from the Acvr1R206H/+ mouse model that mimics the human disease, we demonstrated that activation of the mechanotransductive effectors Rho/ROCK and YAP1 are increased in Acvr1R206H/+ cells. We show that on softer substrates, a condition associated with low mechanical signaling, the morphology of Acvr1R206H/+ cells is similar to the morphology of control Acvr1+/+ cells on stiffer substrates, a condition that activates mechanotransduction. We further determined that Acvr1R206H/+ cells are poised for osteogenic differentiation, expressing increased levels of chondro/osteogenic markers compared with Acvr1+/+ cells. We also identified increased YAP1 nuclear localization in Acvr1R206H/+ cells, which can be rescued by either BMP inhibition or Rho antagonism. Our results establish RhoA and YAP1 signaling as modulators of mechanotransduction in FOP and suggest that aberrant mechanical signals, combined with and as a result of the increased BMP pathway signaling through mutant ACVR1, lead to misinterpretation of the cellular microenvironment and a heightened sensitivity to mechanical stimuli that promotes commitment of Acvr1R206H/+ progenitor cells to chondro/osteogenic lineages.

Dataset Information

Nanofibers Regulate Single Bone Marrow Stem Cell Osteogenesis via FAK/RhoA/YAP1 Pathway.

Publications

Nanofibers Regulate Single Bone Marrow Stem Cell Osteogenesis via FAK/RhoA/YAP1 Pathway.

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