Document Type

Dissertation

Date of Degree

Fall 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In

Biomedical Engineering

First Advisor

James A. Martin

Abstract

Articular cartilage underwent serious joint injuries seldom repair spontaneously and might progress to post-traumatic osteoarthritis. This is majorly because articular cartilage’s unique properties that lack blood and nerve supply intrinsically. This peculiar structure, in addition, generates an unfavorable environment for certain phagocytes (macrophages, monocytes, neutrophils, etc) to infiltrate to cartilage to scavenge debris from cartilage matrix and cell caused from joint injuries. Therefore, physiological and functional regeneration of damaged cartilage is urgently needed and several clinical techniques have been developed, including microfracture, autograft transplantation, autologous chondrocytes implantation.

We previously identified highly migratory cells emerged and repopulated in cartilage damaged surface after ~10 days of artificial cartilage injury. These cells were later named chondrogenic progenitor cells (CPCs) due to their enhanced potential of chondrogenic differentiation. However, this important finding contrasts the conventional theory that cartilage harbors only one cell type, chondrocytes. Here we hypothesize that CPCs are a distinct cell type in cartilage, and more importantly, one of CPCs’ crucial natures is to phagocytose debris more effectively than chondrocytes.

To test these, we first harvested CPCs from cartilage surfaces, chondrocytes, synovial cells (synoviocytes and synovial fluid cells) for microarray assay to evaluate the closeness among these joint cells on whole gene expression level. Quantitative PCR were then conducted to verify gene expression of certain functional interests. Moreover, debris from cell and extracellular matrix were generated and incubated with CPCs and chondrocytes to compare their phagocytic capacity via multiple experimental assessments.

In confocal microscopy examination, the emergence of CPCs could be clearly observed after cartilage injury. Aside from their distinguishable morphology compared to chondrocyte, CPCs possess several vital properties including highly migratory, chemotactic, clonogenic. Microarray data revealed that CPCs, from gene expression profile, are distinctively isolated from chondrocytes and are more akin to synovial cells. Additionally, the series of phagocytosis related experiments showed that CPCs are dramatically superior to chondrocytes in engulfing debris, along with enhanced lysosomal activities indicating the following debris degradation.

Taken all these data together, CPCs, activated by cartilage injury, emerged and migrated to damaged sites. They are a distinct cell type residing in cartilage apart from chondrocytes. Their enhanced capacity to sustainably phagocytose and clear debris provides a novel insight for cartilage regeneration and prevention of osteoarthritis.

Keywords

cartilage regeneration, chondrocytes, chondrogenic progenitor cells, osteoarthritis, phagocytosis

Pages

xv, 105

Bibliography

99-105

Copyright

Copyright © 2016 Cheng Zhou

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