Biology subjects

Tower, R. J.

Publications and source records attributed to Tower, R. J..

5 recordsLinked to original sources

bioRxiv2024

Spatial Transcriptomics Reveals Inflammation and Trans-differentiation States of Acute Myeloid Leukemia in Extramedullary and Medullary Tissues

Acute myeloid leukemia (AML) is a heterogeneous disease of the bone marrow (medullary) but can also involve extramedullary tissues. While single cell dynamics of AML in suspension are previously explored, a comprehensive spatial transcriptomic assessment in AML remain underexplored. Here, we used Visium spatial transcriptomics to resolve medullary and extramedullary AML environments. We reveal spatial co-localization of monocytes and granulocyte-monocyte progenitors with leukemic populations in the bone marrow, sharing molecular signatures with extramedullary sites. Cell-cell communication via the CXCL12- CXCR4 axis correlated with PI3K/AKT/mTOR signaling in high inflammatory niches. Trans- differentiation states were concentrated in AML-infiltrated regions, with committed-like AML populations present in inflammatory niches and away from the trabeculae, while primitive-like AML cells localized near the endosteal niche. We validated these findings in GeoMx-based Digital Spatial profiling (DSP). Our study applied multimodal spatial transcriptomic approaches to characterize the spatial hierarchy and microenvironmental dynamics of AML differentiation states. We also demonstrated the feasibility of applying Visium-based spatial transcriptomics in decalcified bone tissues.

cancer biology↗

bioRxiv2024

Mapping Somatosensory Afferent Circuitry to Bone Identifies Neurotrophic Signals Required for Fracture Healing

The profound pain accompanying bone fracture is mediated by somatosensory neurons, which also appear to be required to initiate bone regeneration following fracture. Surprisingly, the precise neuroanatomical circuitry mediating skeletal nociception and regeneration remains incompletely understood. Here, we characterized somatosensory dorsal root ganglia (DRG) afferent neurons innervating murine long bones before and after experimental long bone fracture in mice. Retrograde labeling of DRG neurons by an adeno-associated virus with peripheral nerve tropism showed AAV-tdT signal. Single cell transcriptomic profiling of 6,648 DRG neurons showed highest labeling across CGRP+ neuron clusters (6.9-17.2%) belonging to unmyelinated C fibers, thinly myelinated A{delta} fibers and A{beta}-Field LTMR (9.2%). Gene expression profiles of retrograde labeled DRG neurons over multiple timepoints following experimental stress fracture revealed dynamic changes in gene expression corresponding to the acute inflammatory (S100a8, S100a9) and mechanical force (Piezo2). Reparative phase after fracture included morphogens such as Tgfb1, Fgf9 and Fgf18. Two methods to surgically or genetically denervate fractured bones were used in combination with scRNA-seq to implicate defective mesenchymal cell proliferation and osteodifferentiation as underlying the poor bone repair capacity in the presence of attenuated innervation. Finally, multi-tissue scRNA-seq and interactome analyses implicated neuron-derived FGF9 as a potent regulator of fracture repair, a finding compatible with in vitro assessments of neuron-to-skeletal mesenchyme interactions.

cell biology↗

bioRxiv2022

NELL-1 regulates the matrisome to alter osteosarcoma disease progression

Sarcomas produce abnormal extracellular matrix (ECM) which in turn provides instructive cues for cell growth and invasion. Neural EGF Like-Like molecule 1 (NELL1) is a secreted glycoprotein characterized by its non-neoplastic osteoinductive effects, yet highly expressed in skeletal sarcomas. Here, NELL1 gene deletion markedly reduced invasive behavior across human osteosarcoma (OS) cell lines. This resulted in reduced OS disease progression, inhibited metastatic potential and improved survival in a xenograft model. These observations were recapitulated with Nell1 conditional knockout in mouse models of p53/Rb driven sarcomagenesis, including reduced tumor frequency, and extended tumor free survival. Transcriptomic and phospho-proteomic analysis demonstrated that NELL1 loss skews the expression of matricellular proteins associated with reduced FAK signaling. Culture on OS enriched matricellular proteins reversed phenotypic and signaling changes among NELL1 knockout sarcoma cells. These findings in mouse and human models suggest that NELL1 expression alters the sarcoma matrix, thereby modulating cellular invasive potential and prognosis. Disruption of NELL1 signaling may represent a novel therapeutic approach to short circuit sarcoma disease progression.

cancer biology↗

bioRxiv2021

Myeloid-to-mesenchymal NGF-p75 signaling coordinates skeletal cell migration during repair

Bone regeneration following injury is initiated by inflammatory signals and occurs in association with infiltration by sensory nerve fibers. Together, these events are believed to coordinate angiogenesis and tissue reprogramming, but the mechanism of coupling immune signals to re-innervation and osteogenesis is unknown. Here, we found that NGF is expressed following cranial bone injury and signals via p75 in resident mesenchymal osteogenic precursors to impact their migration into the damaged tissue. Mice lacking Ngf in myeloid cells demonstrated reduced migration of osteogenic precursors to the injury site with consequently delayed bone healing. These features were phenocopied by mice lacking p75 in Pdgfra+ osteoblast precursors. Single-cell transcriptomics identified mesenchymal subpopulations with potential roles in cell migration and immune response, altered in the context of p75 deletion. Together, these results identify the role of p75 signaling pathway in coordinating skeletal cell migration during early bone repair.

cell biology↗

bioRxiv2019

Single cell transcriptomics identifies a unique adipocyte population that regulates bone marrow environment

Bone marrow mesenchymal lineage cells are a heterogeneous cell population involved in bone homeostasis and diseases such as osteoporosis. While it is long postulated that they originate from mesenchymal stem cells (MSCs), the true identity of MSCs and their in vivo bifurcated differentiation routes into osteoblasts and adipocytes remain poorly understood. Here, by employing single cell transcriptome analysis, we identified MSCs and delineated their bi-lineage differentiation paths in young, adult and aging mice. Among several newly discovered mesenchymal subpopulations, one is a distinct population of adipose-lineage cells that we named marrow environment regulating adipose cells (MERAs). MERAs are non-proliferative, post-progenitor cells that express many mature adipocyte markers but are devoid of lipid droplets. They are abundant in the bone marrow of young mice, acting as pericytes and stromal cells that form numerous connections among themselves and with other cells inside bone, including endothelial cells. Genetic ablation of MERAs disrupts marrow vessel structure, promotes de novo bone formation. Taken together, MERAs represent a unique population of adipose lineage cells that exist only in the bone marrow with critical roles in regulating bone and vessel homeostasis.

cell biology↗