TET1 Regulates Skeletal Stem–Cell Mediated Cartilage Regeneration

Abstract

ObjectiveAdult 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.MethodsWe 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.ResultsLoss 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.ConclusionWhile 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.

Melatonin is a potential novel analgesic agent for osteoarthritis: Evidence from cohort studies in humans and preclinical research in rats

“…Previous studies have shown that melatonin could promote the synthesis of cartilage matrix, inhibit chondrocyte apoptosis, dampen inflammatory response, rescue the mitochondrial functions, and suppress matrix degradation through a variety of signaling pathways, for example, transforming growth factor β, mitogen-activated protein kinase, or nuclear factor-κB signaling pathways. 34,35 Effect of melatonin on pain and cartilage may explain its potential protective effect on the risk of joint replacement and incident SxOA. Synovitis and macrophages have prominent roles in pain from OA.…”