TET1 regulates skeletal stem cell (SSC) mediated cartilage regeneration
Akshay Pandey, Malachia Hoover, Mamta Singla, Yudhishtar Bedi, Hunter Storaci, Stuart B. Goodman, Charles Chan, Nidhi Bhutani- Immunology
- Rheumatology
- Immunology and Allergy
Objective
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.
Methods
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.
Results
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.
Conclusion
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.