Date of Degree
PhD (Doctor of Philosophy)
James A. Martin
First Committee Member
Michael J Schnieders
Second Committee Member
Edward A Sander
Third Committee Member
Nicole M Grosland
Fourth Committee Member
Michael A Mackey
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.
Osteoarthritis (OA) is one of most worldwide degenerative joint diseases dramatically affecting human health, over 27 million people in US are suffering from OA. Although aging is considered as the primary cause for OA, the pathogenesis of OA is still poorly understood. In addition, cartilage injures caused from continuous overuse and acute trauma often progress to OA. Due to the complicated and unique properties (lack of nerve and blood supply), cartilage has extremely limited capacity to repair spontaneously after injury.A distinct cell type, chondrogenic progenitor cells (CPCs), have been identified on cartilage surface post injury, they function differently compared to chondrocytes, native cartilage cells. In this study, we focused on distinguishing CPCs from chondrocytes on global gene expression level. We also investigated how cartilage scavenges debris from injury. Since professional phagocytes (macrophage, monocytes, neutrophils, etc) are extremely unlikely to relocate to injured cartilage surface, we speculated that CPCs could act the scavenger role in injured cartilage. From the heat map generated from microarray, the distinctive relation between CPCs and chondrocyte was revealed on global gene expression level. Additionally, CPCs are more akin to certain cells from joints (e.g. synoviocytes and synovial fluid cells). Based on a series of phagocytosis related experiments, we found that CPCs, compared to chondrocytes, could scavenge debris from cartilage injury more efficiently to the level of professional phagocytes.
cartilage regeneration, chondrocytes, chondrogenic progenitor cells, osteoarthritis, phagocytosis
xv, 105 pages
Includes bibliographical references (pages 99-105).
Copyright © 2016 Cheng Zhou
Zhou, Cheng. "Enhanced phagocytic capacity endows chondrogenic progenitor cells with a novel scavenger function within injured cartilage." PhD (Doctor of Philosophy) thesis, University of Iowa, 2016.