Multi-signals involved in human joint homeostasis

Xiaobin Huang

Research output: ThesisPhD Thesis - Research UT, graduation UT

127 Downloads (Pure)

Abstract

Osteoarthritis (OA) is one universal chronic joint disease. Due to the avascular and aneural properties, once it is irreparably damaged, external intervention in the form of cartilage repair is desired. Chondrocytes is the only one cell type in the articular cartilage to produce the matrix. Autologous chondrocyte implantation (ACI) and hMSC based cell therapy have been shown promising options. Multiple cytokines and signaling pathways have been shown to involved in the regulation of chondrocytes homeostasis and cartilage development. The aim of this thesis is to study the chondrogenic differentiation of human MSCs, redifferentiation of human chondrocytes and the possible BMP7 based tissue engineering by focus on Wnt signaling, hypoxia induced signaling, transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling, to provide more mechanisms in the ACI and hMSCs based cell therapy for OA.

In chapter 2, we provided a comprehensive review on signal pathways in the hypertrophy of MSCs derived chondrocytes and chondrocytes. In chapter 3, we investigated the presence of WNT antagonists DKK1, FRZB in synovial fluid (SF) and serum respectively from OA patients and correlate these antagonists with pro-inflammatory cytokines in SF. We further elucidated the effects of Wnt activator and Wnt inhibitor on the chondrogenic differentiation of hMSCs by continuous inhibiting or activation Wnt signaling in chapter 4. In chapter 5, we investigated the effects of oxygen on three-dimensional redifferentiation in both healthy and OA chondrocyte with or without IL1β stimulation. In chapter 6, we identified the effects of exogenous BMP7 and TGF-β3 on the redifferentiation of OA chondrocytes under hypoxia. In chapter 7, we generated biofunctional VHH antodoby (bihead) that can specific bind BMP-7 and HA simultaneously. In this study, BMP7 was efficiently direct to the mineralized skeleton through binding bihead after injection into mice.

All together, this thesis evaluated the Wnt signaling in synovial fluid and the differentiation of hMSCs, assessed the redifferentiation of human chondrocytes effected by hypoxia, inflammatory factor IL1β, BMP7 and TGFβ3, elucidated the production of bihead VHHs and its application in tissue engineering. We believe the findings from this thesis may offer great potential in cell-based cartilage engineering.
Original languageEnglish
Awarding Institution
  • University of Twente
Supervisors/Advisors
  • Karperien, H.B.J., Supervisor
Award date19 Jan 2018
Place of PublicationEnschede
Publisher
Print ISBNs978-90-365-4466-5
DOIs
Publication statusPublished - 19 Jan 2018

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