Showing papers by "Joshua D. Welch published in 2023"
TL;DR: In this paper , the identity of skeletal stem cells (SSCs) in young bone marrow and how they coordinate active bone formation remains unclear. But it is well-known that osteoblasts and chondrocytes provide a major source of bone-forming osteobasts in adult and aged bone marrow.
Abstract: The bone marrow contains various populations of skeletal stem cells (SSCs) in the stromal compartment, which are important regulators of bone formation. It is well-described that leptin receptor (LepR)+ perivascular stromal cells provide a major source of bone-forming osteoblasts in adult and aged bone marrow. However, the identity of SSCs in young bone marrow and how they coordinate active bone formation remains unclear. Here we show that bone marrow endosteal SSCs are defined by fibroblast growth factor receptor 3 (Fgfr3) and osteoblast-chondrocyte transitional (OCT) identities with some characteristics of bone osteoblasts and chondrocytes. These Fgfr3-creER-marked endosteal stromal cells contribute to a stem cell fraction in young stages, which is later replaced by Lepr-cre-marked stromal cells in adult stages. Further, Fgfr3+ endosteal stromal cells give rise to aggressive osteosarcoma-like lesions upon loss of p53 tumor suppressor through unregulated self-renewal and aberrant osteogenic fates. Therefore, Fgfr3+ endosteal SSCs are abundant in young bone marrow and provide a robust source of osteoblasts, contributing to both normal and aberrant osteogenesis.
3 citations
TL;DR: In this paper , the role of VPR in HIV-infection of primary macrophages was examined using single-cell RNA sequencing to capture the transcriptional changes during an HIV-1 spreading infection plus and minus Vpr.
Abstract: The HIV-1 accessory protein, Vpr, is an enigmatic protein required for efficient spread of HIV from macrophages to T cells, a necessary step for propagation of infection. To illuminate the role of Vpr in HIV-infection of primary macrophages, we used single-cell RNA sequencing to capture the transcriptional changes during an HIV-1 spreading infection plus and minus Vpr. We found that Vpr reprogramed HIV-infected macrophage gene expression by targeting the master transcriptional regulator, PU.1. PU.1 was required for efficient induction of the host innate immune response to HIV, including upregulation of ISG15, LY96, and IFI6. In contrast, we did not observe direct effects of PU.1 on HIV gene transcription. Single cell gene expression analysis also revealed Vpr countered an innate immune response to HIV-infection within bystander macrophages via a PU.1-independent mechanism. The capacity of Vpr to target PU.1 and disrupt the anti-viral response was highly conserved across primate lentiviruses including HIV-2 and several SIVs. By demonstrating how Vpr overcomes a critical early warning system of infection, we identify a crucial reason why Vpr is necessary for HIV infection and spread.
1 citations