Culture-expanded articular chondrocytes: a potential cellular therapeutic for osteoarthritis with MSC-like properties
Date
2022
Authors
Liebig, Bethany Ellen, author
Goodrich, Laurie, advisor
Kisiday, John, advisor
Regan, Daniel, committee member
Santangelo, Kelly, committee member
McGilvray, Kirk, committee member
Bahney, Chelsea, committee member
Journal Title
Journal ISSN
Volume Title
Abstract
Osteoarthritis (OA) is a highly prevalent and debilitating joint disease in horses, dogs, and humans. OA affects more than 303 million people globally with an annual economic loss to Americans approaching $200 billion. It has a considerable impact on the patient, resulting in pain and disability and more than 1 million people undergo knee arthroscopy or joint replacement surgery each year due to end-stage OA in the United States. Therefore, OA therapies that produce lasting symptom- and disease-modifying effects are a medical priority. Mesenchymal stromal cells (MSCs) are considered 'medicinal signaling cells' that have been postulated to treat OA by reducing inflammation and restoring joint function. However, IA injection of MSCs into diseased human or companion animal joints has demonstrated only a modest benefit to date, as symptom-modifying effects are often temporary, and evidence of disease-modification has been minimal. It has been reported that culture-expanded chondrocytes (CECs) can assume many of the hallmark properties of MSCs, such as immunomodulation and immunophenotype. However, unlike MSCs, chondrocytes are known to thrive in suspension, which is important as IA injections release cells into synovial fluid. The goal of this research aims to characterize the growth, immunomodulatory properties, and gene expression of equine CECs as a function of expansion in vitro as well as CEC persistence in the joint after intra-articular injection using a validated model of OA in rats. Additional goals of this research are to 1) determine how CECs may (persistence) or may not (immunomodulation and molecular fingerprint) differ from bone marrow derived MSCs, and 2) compare cellular properties of CECs across age to determine an ideal donor for generating allogeneic therapies. The results shown in chapters 2 and 3 indicate that chondrocytes retain a strong propensity for immunomodulation, that increases with expansion and dedifferentiation does not coincide with other temporal changes in gene expression. Further, these data do not indicate a benefit of neonatal donors. Future in vitro studies should further characterize the immunomodulatory, redifferentiation (chondrogenic) and angiogenic potential of CECs. The preliminary results described in chapter 4 indicate that CECs may have greater persistence than MSCs in the first 3 days post IA injection. Future in vivo studies should focus on determining the symptom- and disease-modifying effects following IA injection of CECs in relevant preclinical models, such as the rodent, horse, and dog.
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Embargo Expires: 01/09/2025
Subject
chondrocytes
osteoarthritis
mesenchymal stromal cells
cellular therapies