Tamariz-Amador, L.-E. | Search bioRxiv

bioRxiv2025

Single-cell transcriptional profiling reveals a novel RAB13+ endothelial subpopulation and profibrotic mesenchymal cells in the aged human bone marrow

The bone marrow (BM) microenvironment plays a crucial role in regulating hematopoiesis, yet the molecular changes associated with aging in humans remain poorly understood. Using single-cell RNA sequencing, we uncovered transcriptional shifts in BM endothelial cells (EC) and mesenchymal stem cells (MSC) during aging. Aged sinusoidal EC exhibited a prothrombotic phenotype with compromised mitochondrial and vascular function. Additionally, we identified a novel arterial EC subset, emerging in aged individuals, characterized by RAB13 expression and associated with transcriptional regulatory processes. MSC from aged subjects displayed impaired matrix remodeling and epithelial-mesenchymal transition, driven partly by a subpopulation of THY1+ profibrotic cells absent in younger individuals. Finally, immunofluorescent imaging and spatial transcriptomics confirmed the presence of these aging-associated cells in BM samples from aged individuals. In summary, this work provides a comprehensive view of the transcriptional landscape, cellular interactions, and spatial organization of aged EC and MSC, offering novel insights and potential targets that could be exploited for preventing age-associated changes in humans. TeaserAging reshapes the bone marrow with emergence of RAB13+ endothelial cells and profibrotic stromal cells altering tissue function.

molecular biology↗

bioRxiv2024

Transcriptional Characterization of the Stromal and Endothelial Bone Marrow Microenvironment during Progression from MGUS to Multiple Myeloma

The role of the non-immune bone marrow microenvironment (BME) in the transition from monoclonal gammopathy of undetermined significance (MGUS) into clinically active multiple myeloma (MM) remains incompletely defined. To address this, we transcriptionally profiled endothelial cells (EC), mesenchymal stem cells (MSC) and MM cells at single-cell resolution from two genetically engineered mouse models (BIc{gamma}1 and MIc{gamma}1) that recapitulate MGUS to MM progression. Our analysis revealed distinct transcriptional trajectories in EC and MSC, uncovering stage-specific BME-PC interactions shaping disease progression. EC acquired a stress phenotype during MGUS transitioning to angiogenesis in MM, while MSC exhibited early impaired differentiation capacity during MGUS that persisted in MM. Notably, an interferon (IFN)-associated MM signature was detected in EC and MSC from the BIc{gamma}1 model but was absent in the more aggressive MIc{gamma}1 model. Treatment with bortezomib, lenalidomide, and dexamethasone remodeled the BME by suppressing MM-IFN signaling, promoting an adaptive response in EC, and restoring osteogenic potential in MSC-- shifting the niche toward a less tumor-permissive state. Importantly, the MM-IFN signature was validated in patients across the MGUS-to-MM spectrum, supporting the translational relevance of our findings. Together, these data define novel dynamic and targetable alterations in the non-immune BME during myeloma progression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/589777v5_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1a0ef62org.highwire.dtl.DTLVardef@c44014org.highwire.dtl.DTLVardef@4b1df6org.highwire.dtl.DTLVardef@19c29a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗