Yudhishtar Bedi

All Publications

• Multi-parametric profiling of circulating immune cells identifies an expansion of CD25hi switched memory B cells in Osteoarthritis. Arthritis & rheumatology (Hoboken, N.J.) Sahu, N., Bedi, Y. S., Grandi, F., Maloney, W. J., Chu, C. R., Bhutani, N. 2025

  Abstract

  Osteoarthritis (OA) is a chronic, debilitating disease with no available disease-modifying drugs. Biomarker identification in OA patients has hitherto been limited to serum proteins and bulk epigenomic feature identification.Peripheral blood mononuclear cells (PBMC) from 21 healthy donors, 17 OA patients, and 10 patients with degenerative meniscal tears (DMT) were immunophenotyped at single-cell resolution by mass cytometry by time-of-flight (cyTOF) using a 29-marker panel to identify OA-associated features in the circulating immune cells. Single-cell RNA sequencing was utilized to discern mechanistic attributes of perturbed immune cell populations in OA.Comparison of healthy donors and OA patients' PBMC revealed distinct perturbations in OA. While subsets of naive B cells were depleted, switched memory B cells were significantly expanded in OA including a CD25hiCXCR5hiCD27+IgD- subpopulation. Single cell-RNA sequencing revealed a dysfunction of IL2/Stat3 and TNF signaling in the CD25hi switched memory B cells in OA. A similar expansion of CD25hi switched memory B cells was observed in patients with DMT, a population at enhanced risk for OA.A CD25hi switched memory B cell population was identified to be a potential cellular biomarker for OA that can be detected in early stages of OA in the readily accessible circulating blood cells.

  View details for DOI 10.1002/art.43186

  View details for PubMedID 40229860

• Laminin-associated integrins mediate Diffuse Intrinsic Pontine Glioma infiltration and therapy response within a neural assembloid model. Acta neuropathologica communications Sinha, S., Huang, M. S., Mikos, G., Bedi, Y., Soto, L., Lensch, S., Ayushman, M., Bintu, L., Bhutani, N., Heilshorn, S. C., Yang, F. 2024; 12 (1): 71

  Abstract

  Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive and fatal pediatric brain cancer. One pre-requisite for tumor cells to infiltrate is adhesion to extracellular matrix (ECM) components. However, it remains largely unknown which ECM proteins are critical in enabling DIPG adhesion and migration and which integrin receptors mediate these processes. Here, we identify laminin as a key ECM protein that supports robust DIPG cell adhesion and migration. To study DIPG infiltration, we developed a DIPG-neural assembloid model, which is composed of a DIPG spheroid fused to a human induced pluripotent stem cell-derived neural organoid. Using this assembloid model, we demonstrate that knockdown of laminin-associated integrins significantly impedes DIPG infiltration. Moreover, laminin-associated integrin knockdown improves DIPG response to radiation and HDAC inhibitor treatment within the DIPG-neural assembloids. These findings reveal the critical role of laminin-associated integrins in mediating DIPG progression and drug response. The results also provide evidence that disrupting integrin receptors may offer a novel therapeutic strategy to enhance DIPG treatment outcomes. Finally, these results establish DIPG-neural assembloid models as a powerful tool to study DIPG disease progression and enable drug discovery.

  View details for DOI 10.1186/s40478-024-01765-4

  View details for PubMedID 38706008

  View details for PubMedCentralID 4161623

• TET1 regulates skeletal stem cell (SSC) mediated cartilage regeneration. Arthritis & rheumatology (Hoboken, N.J.) Pandey, A., Hoover, M., Singla, M., Bedi, Y., Storaci, H., Goodman, S. B., Chan, C., Bhutani, N. 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