All Publications
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Inhibition of 15-hydroxy prostaglandin dehydrogenase promotes cartilage regeneration.
Science (New York, N.Y.)
2025: eadx6649
Abstract
Aging or injury to the joints can lead to cartilage degeneration and osteoarthritis (OA), for which there are limited effective treatments. We found that expression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH) is increased in the articular cartilage of aged or injured mice. Both systemic and local inhibition of 15-PGDH with a small molecule inhibitor (PGDHi) led to regeneration of articular cartilage and reduction in OA-associated pain. Using single cell RNA-sequencing and multiplexed immunofluorescence imaging of cartilage, we identified the major chondrocyte subpopulations. Inhibition of 15-PGDH decreased hypertrophic-like chondrocytes expressing 15-PGDH and increased extracellular matrix-synthesizing articular chondrocytes. Cartilage regeneration appears to occur through gene expression changes in pre-existing chondrocytes, rather than stem or progenitor cell proliferation. 15-PGDH inhibition could be a potential disease-modifying and regenerative approach for osteoarthritis.
View details for DOI 10.1126/science.adx6649
View details for PubMedID 41308124
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Targeting an inflammation-amplifying cell population can attenuate osteoarthritis-associated pain.
Arthritis research & therapy
2024; 26 (1): 53
Abstract
BACKGROUND: Understanding of pain in osteoarthritis, its genesis, and perception is still in its early stages. Identification of precise ligand-receptor pairs that transduce pain and the cells and tissues in which they reside will elucidate new therapeutic approaches for pain management. Our recent studies had identified an inflammation-amplifying (Inf-A) cell population that is expanded in human OA cartilage and is distinctive in the expression of both IL1R1 and TNF-R2 receptors and active Jnk signaling cascade.METHODS: In this study, we have tested the function of the cartilage-resident IL1R1+TNF-R2+ Inf-A cells in OA. We have identified that the IL1R1+TNF-R2+ Inf-A cells expand in aged mice as well as after anterior cruciate ligament tear upon tibia loading and OA initiation in mice. We targeted and modulated the Jnk signaling cascade in InfA through competitive inhibition of Jnk signaling in mice and human OA explants and tested the effects on joint structure and gait in mice.RESULTS: Modulation of Jnk signaling led to attenuation of inflammatory cytokines CCL2 and CCL7 without showing any structural improvements in the joint architecture. Interestingly, Jnk inhibition and lowered CCL2 and 7 are sufficient to significantly improve the gait parameters in treated PTOA mice demonstrating reduced OA-associated pain. Consistent with the mice data, treatment with JNK inhibitor did not improve human OA cartilage explants.CONCLUSION: These studies demonstrate that Inf-A, an articular-cartilage resident cell population, contributes to pain in OA via secretion of CCL2 and 7 and can be targeted via inhibition of Jnk signaling.
View details for DOI 10.1186/s13075-024-03284-y
View details for PubMedID 38368390
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TET1 regulates skeletal stem cell (SSC) mediated cartilage regeneration.
Arthritis & rheumatology (Hoboken, N.J.)
2023
Abstract
Adult skeletal stem cells (SSC) give rise to chondrocytes, osteocytes and stromal cells as progeny have been shown to contribute to cartilage regeneration in Osteoarthritis (OA). Understanding extrinsic and intrinsic regulators of SSC fate and function can therefore identify putative candidate factors to enhance cartilage regeneration. This study explores how the DNA hydroxymethylase, TET1 regulates SSC function in OA.We investigated the differences in SSC lineage tree and differentiation potential in neonatal and adult Tet1 +/+ and Tet1-/- mice, with and without injury and upon OA induction and progression. Using RNA-seq, the transcriptomic differences between SSC and Bone, cartilage and stromal progenitor cells (BCSP) were identified in Tet1 +/+ mice and Tet1-/- mice.Loss of Tet1 skewed the SSC lineage tree by expanding the SSC pool and enhanced the chondrogenic potential of SSC and BCSP. Tet1 inhibition led to enhanced chondrogenesis in in human SSC and chondroprogenitors (CP) isolated from human cartilage. Importantly, TET1 inhibition in vivo in late stages of a mouse model of Osteoarthritis (OA) led to increased cartilage regeneration. Transcriptomic analyses of SSC and BCSP lacking Tet1 revealed pathway alterations in TGFβ signaling, melatonin degradation and cartilage development associated genes. Lastly, we report that use of hormone melatonin can dampen inflammation and improve cartilage health.While Tet1 is a broad epigenetic regulator, Melatonin can mimic the ability of TET1 inhibition to enhance the chondrogenic ability of skeletal stem cells. Melatonin administration has the potential to be an attractive stem cell based therapy for cartilage regeneration.
View details for DOI 10.1002/art.42678
View details for PubMedID 37610277
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A Quick and Efficient Method for the Generation of Immunomodulatory MSC from Human iPSC.
Tissue engineering. Part A
2021
Abstract
Mesenchymal stromal cells (MSC) have been widely investigated for their regenerative capacity, anti-inflammatory properties and beneficial immunomodulatory effects across multiple clinical indications. Nevertheless, their widespread clinical utilization is limited by the variability in MSC quality, impacted by donor age, metabolism and disease. Human induced pluripotent stem cells (hiPSC) generated from readily accessible donor tissues, are a promising source of stable and rejuvenated MSC but differentiation methods generally require prolonged culture and result in low frequencies of stable MSC. To overcome this limitation, we have optimized a quick and efficient method for hiPSC differentiation into foot-print free MSC (hiMSC) in this study. This method capitalizes on the synergistic action of growth factors Wnt3a and Activin A with BMP4, leading to an enrichment of MSC after only 4 days of treatment. These hiMSC demonstrate a significant upregulation of mesenchymal stromal markers (CD105+, CD90+, CD73 and CDH) comparable to bone marrow-derived MSC, with reduced expression of the pluripotency genes (Oct-4, c-Myc, Klf4 and Nanog) compared to hiPSC. Moreover, they show improved proliferation capacity in culture without inducing any teratoma formation in vivo. Osteogenesis, chondrogenesis and adipogenesis assays confirmed the ability of hiMSC to differentiate into the three different lineages. Secretome analyses showed cytokine profiles comparable to bone marrow-derived MSC. Encapsulated hiMSC in alginate beads co-cultured with osteoarthritic (OA) cartilage explants showed robust immunomodulation, with stimulation of cell growth and proteoglycan production in OA cartilage. Our quick and efficient protocol for derivation of hiMSC from hiPSC, and their encapsulation in microbeads therefore, presents a reliable and reproducible method to boost the clinical applications of MSC.
View details for DOI 10.1089/ten.TEA.2021.0172
View details for PubMedID 34693750