Chan, B. S. | bioRxiv Science

bioRxiv2026

Intermittent parathyroid hormone employs autonomous and non-autonomous mechanisms to drive osteogenesis from Ebf3-expressing skeletal progenitor cells

How systemic hormonal signals coordinate stem cell fate decisions in adult tissues remains incompletely understood. In bone marrow, Cxcl12-abundant reticular (CAR) cells, marked by Early B-cell Factor 3 (Ebf3) expression, are multipotent mesenchymal progenitors that maintain the hematopoietic stem cell niche and serves as a major osteoblast progenitor source during adult bone remodeling. Using inducible lineage tracing coupled with single-cell transcriptomics and conditional genetics in mice, we show that intermittent parathyroid hormone (iPTH; teriparatide) drives osteogenesis from CAR cells by simultaneously engaging cell-intrinsic and cell-extrinsic mechanisms. Directly, iPTH suppresses lineage-enforcing transcription factors Ebf3, Ebf1, and Foxc1, thereby destabilizing progenitor identity and priming CAR cells for osteogenic commitment. Simultaneously, iPTH stimulates osteoclastic bone resorption, releasing TGF{beta} which recruits these primed progenitors to bone surfaces, a process abolished by osteoclast depletion. Preventing CAR cell maturation via Sp7 deletion abrogates iPTH-induced bone gain, establishing these progenitors as essential mediators of bone anabolism. This coupled mechanism, in which intrinsic transcriptional priming converges with extrinsic niche remodeling, is conserved in human CAR cells from teriparatide-treated postmenopausal women, which show concordant suppression of EBF3 and FOXC1 and elevated TGF{beta}-responsive gene signatures. These findings reveal a general principle by which a systemic hormone orchestrates tissue remodeling through simultaneous reprogramming of progenitor identity and remodeling of the niche microenvironment.

physiology↗

bioRxiv2022

Mutations of SARS-CoV-2 variants of concern escaping Spike-specific T cells

The amino acid (AA) mutations that characterise the different variants of concern (VOCs), which replaced the ancestral SARS-CoV-2 Wuhan-Hu-1 isolate worldwide, provide biological advantages such as increased infectivity and partial escape from humoral immunity. Here we analysed the impact of these mutations on vaccination- and infection-induced Spike-specific T cells. We confirmed that, in the majority of infected or vaccinated individuals, different mutations present in a single VOC (Delta) or a combined mosaic of more than 30 AA substitutions and deletions found in Alpha, Beta, Gamma, Delta and Omicron VOCs cause modest alteration in the global Spike-specific T cell response. However, distinct numerically dominant Spike-specific CD4 and CD8 T cells preferentially targeted regions affected by AA mutations and do not recognise the mutated peptides. Importantly, some of these mutations, such as N501Y (present in Alpha, Beta, Gamma, and Omicron) and L452R (present in Delta), known to provide biological advantage to SARS-CoV-2 in terms of infectivity also abolished CD8 T cell recognition. Taken together, our data show that while global mRNA vaccine- and infection-induced Spike-specific T cells largely tolerate the diverse mutations present in VOCs, single Spike-specific T cells might contribute to the natural selection of SARS-CoV-2 variants.

immunology↗