Injectable perlecan domain 1-hyaluronan microgels potentiate the cartilage repair effect of BMP2 in a murine model of early osteoarthritis

Srinivasan, Padma Pradeepa; McCoy, Sarah Y.; Jha, Amit K.; Yang, Weidong; Jia, Xinqiao; Farach-Carson, Mary C.; Kirn‐Safran, Catherine B.

doi:10.1088/1748-6041/7/2/024109

Cited by 67 publications

(55 citation statements)

References 47 publications

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“…MSCs have been induced to differentiate along the chondrogenic pathway using BMPs (61,64). BMP2 has been demonstrated as among the most chondrogenic growth factors, promoting chondrocyte differentiation in vitro and augmenting articular cartilage healing in vivo (6,30,40,50,52). Bone marrow-derived mesenchymal stem cells were shown to produce hyaline-like cartilage tissue (66).…”

Section: Discussionmentioning

confidence: 99%

Reversibly Immortalized Mouse Articular Chondrocytes Acquire Long-Term Proliferative Capability While Retaining Chondrogenic Phenotype

et al. 2015

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Cartilage tissue engineering holds great promise for treating cartilaginous pathologies including degenerative disorders and traumatic injuries. Effective cartilage regeneration requires an optimal combination of biomaterial scaffolds, chondrogenic seed cells, and biofactors. Obtaining sufficient chondrocytes remains a major challenge due to the limited proliferative capability of primary chondrocytes. Here we investigate if reversibly immortalized mouse articular chondrocytes (iMACs) acquire long-term proliferative capability while retaining the chondrogenic phenotype. Primary mouse articular chondrocytes (MACs) can be efficiently immortalized with a retroviral vector-expressing SV40 large T antigen flanked with Cre/loxP sites. iMACs exhibit long-term proliferation in culture, although the immortalization phenotype can be reversed by Cre recombinase. iMACs express the chondrocyte markers Col2a1 and aggrecan and produce chondroid matrix in micromass culture. iMACs form subcutaneous cartilaginous masses in athymic mice. Histologic analysis and chondroid matrix staining demonstrate that iMACs can survive, proliferate, and produce chondroid matrix. The chondrogenic growth factor BMP2 promotes iMACs to produce more mature chondroid matrix resembling mature articular cartilage. Taken together, our results demonstrate that iMACs acquire long-term proliferative capability without losing the intrinsic chondrogenic features of MACs. Thus, iMACs provide a valuable cellular platform to optimize biomaterial scaffolds for cartilage regeneration, to identify biofactors that promote the proliferation and differentiation of chondrogenic progenitors, and to elucidate the molecular mechanisms underlying chondrogenesis.

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Section: Discussionmentioning

confidence: 99%

Reversibly Immortalized Mouse Articular Chondrocytes Acquire Long-Term Proliferative Capability While Retaining Chondrogenic Phenotype

et al. 2015

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“…Many HA-derived medical products have been developed and tested and the readers are referred to recent reviews [17, 175] for in-depth analyses. In this article, we highlight our own experiences in the application of HA-based hydrogels for the repair and regeneration of healthy functional tissues, such as vocal folds [176–179], cartilage [180, 181] and salivary glands [182, 183], as well as the creation of pathological tissue models, such as tumor spheroids [184–186]. …”

Section: Ha In Biomedical Applicationsmentioning

confidence: 99%

Hyaluronan: A simple polysaccharide with diverse biological functions

Dicker¹,

Gurski²,

et al. 2014

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Hyaluronan (HA) is a linear polysaccharide with disaccharide repeats of D-glucuronic acid and N-acetyl-D-glucosamine. It is evolutionary conserved and abundantly expressed in the extracellular matrix (ECM), on the cell surface and even inside cells. Being a simple polysaccharide, HA exhibits an astonishing array of biological functions. HA interacts with various proteins or proteoglycans to organize the ECM and to maintain tissue homeostasis. The unique physical and mechanical properties of HA contribute to the maintenance of tissue hydration, the mediation of solute diffusion through the extracellular space and the lubrication of certain tissues. The diverse biological functions of HA are manifested through its complex interactions with matrix components and resident cells. Binding of HA with cell surface receptors activates various signaling pathways that regulate cell function, tissue development, inflammation, wound healing and tumor progression and metastasis. Taking advantage of the inherent biocompatibility and biodegradability of HA, as well as its susceptibility to chemical modification, researchers have developed various HA-based biomaterials and tissue constructs with promising and broad clinical potential. In this article, we illustrate the properties of HA from a matrix biology perspective by first introducing principles underlying the biosynthesis and biodegradation of HA, as well as the interactions of HA with various proteins and proteoglycans. We next highlight the roles of HA in physiological and pathological states, including morphogenesis, wound healing and tumor metastasis. A deeper understanding of the mechanisms underlying the roles of HA in various physiological processes can provide new insights and tools for the engineering of complex tissues and tissue models.

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“…In this instance, perlecan is likely to appear both to re-establish tissue boundaries, and also to provide a depot for the timed delivery of growth factors needed for new bone formation. Additionally, perlecan domain I has been used as a vehicle for delivery of BMP2 for healing of early lesions in an induced model of osteoarthritis or in bone repair (Decarlo et al, 2012; Srinivasan et al, 2012). …”

Section: Concentration At Tissue Borders In Complex Tissues Of Vermentioning

confidence: 99%

Border patrol: Insights into the unique role of perlecan/heparan sulfate proteoglycan 2 at cell and tissue borders

et al. 2014

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The extracellular matrix proteoglycan (ECM) perlecan, also known as heparan sulfate proteoglycan 2 or HSPG2, is one of the largest (>200 nm) and oldest (>550M years) extracellular matrix molecules. In vertebrates, perlecan’s five-domain structure contains numerous independently folding modules with sequence similarities to other ECM proteins, all connected like cars into one long, diverse complex train following a unique N-terminal domain I decorated with three long glycosaminoglycan chains, and an additional glycosaminoglycan attachment site in the C-terminal domain V. In lower invertebrates, perlecan is not typically a proteoglycan, possessing the majority of the core protein modules, but lacking domain I where the attachment sites for glycosaminoglycan chains are located. This suggests that uniting the heparan sulfate binding growth factor functions of domain I and the core protein functions of the rest of the molecule in domains II-V occurred later in evolution for a new functional purpose. In this review, we surveyed several decades of pertinent literature to ask a fundamental question: Why did nature design this protein uniquely as an extraordinarily long multifunctional proteoglycan with a single promoter regulating expression, rather than separating these functions into individual proteins that could be independently regulated? We arrived at the conclusion that the concentration of perlecan at functional borders separating tissues and tissue layers is an ancient key function of the core protein. The addition of the heparan sulfate chains in domain I likely occurred as an additional means of binding the core protein to other ECM proteins in territorial matrices and basement membranes, and as a means to reserve growth factors in an on-site depot to assist with rapid repair of those borders when compromised, such as would occur during wounding. We propose a function for perlecan that extends its role from that of an extracellular scaffold, as we previously suggested, to that of a critical agent for establishing and patrolling tissue borders in complex tissues in metazoans. We also propose that understanding these unique functions of the individual portions of the perlecan molecule can provide new insights and tools for engineering of complex multi-layered tissues including providing the necessary cues for establishing neotissue borders.

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Injectable perlecan domain 1-hyaluronan microgels potentiate the cartilage repair effect of BMP2 in a murine model of early osteoarthritis

Cited by 67 publications

References 47 publications

Reversibly Immortalized Mouse Articular Chondrocytes Acquire Long-Term Proliferative Capability While Retaining Chondrogenic Phenotype

Reversibly Immortalized Mouse Articular Chondrocytes Acquire Long-Term Proliferative Capability While Retaining Chondrogenic Phenotype

Hyaluronan: A simple polysaccharide with diverse biological functions

Border patrol: Insights into the unique role of perlecan/heparan sulfate proteoglycan 2 at cell and tissue borders

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