Biology subjects

Noom, A.

Publications and source records attributed to Noom, A..

2 recordsLinked to original sources

bioRxiv2025

Distinct matrix viscoelasticity in bone fracture hematoma steers macrophage polarization

Physical properties of the extracellular matrix (ECM) are key regulators of cellular behavior. Following injury, the formation of a hematoma establishes a provisional niche that initiates and regulates healing responses. However, the influence of hematoma viscoelastic properties on immune cell behavior remains poorly understood. Here, we show that distinct ECM viscoelastic properties of the maturing fracture hematoma steer macrophage polarization from pro-inflammatory to pro-regenerative characteristics. Tissue analyses of ex vivo human samples revealed that hematoma viscoelastic properties change with ECM remodeling during healing progression, with the late-phase stress relaxation time constant, {tau}2, increasing significantly with days post-injury. Using alginate hydrogels in 3D culture, we engineered extracellular microenvironments with tunable {tau}2 but constant stiffness to study their role in macrophage polarization. Our data demonstrate that ECM {tau}2 properties guide macrophage phenotype, characterized by high {tau}2 promoting pro-inflammatory activation, while low {tau}2 supported anti-inflammatory phenotypes. This regulation of macrophage polarization by ECM stress relaxation properties persists even under toll-like receptor-coactivation. Single-cell RNA sequencing revealed distinct transcriptional programs associated with different ECM {tau}2 values, with many of the differentially expressed genes related to metabolic processes. The transcriptomic profiles of macrophages primed by different ECM {tau}2 aligned with in vivo healing trajectories, with the gene signature score of the low ECM {tau}2 decreasing over time. Our findings uncover the immune-regulatory function of specific hematoma stress relaxation properties associated with healing progress after injury, and suggest {tau}2 as potential mechanobiological target to be leveraged in novel biomaterials-based regenerative therapies.

bioengineering↗

bioRxiv2025

The cortical microenvironment drives early immune organization and controls early osteoclastogenesis in bone healing

Bone regeneration is a complex, tightly-regulated process involving coordinated interactions of immune and stromal cells. Early phases of healing rely on the timely clearance of debris, a task primarily carried out by macrophages and osteoclasts. However, the sequence of events leading to the presence of osteoclasts at the fracture site and how this is shaped by local tissue microenvironments remains poorly understood, particularly at single-cell and spatial resolution. Using single-cell RNA sequencing and multi-epitope ligand cartography, we mapped the spatial organization of distinct cell compartments engaged in early fracture healing in both young and aged mice at the start of healing. Surprisingly, we found that young mice exhibited an increased presence of activated osteoclasts at day 7, concentrated within the cortical niche. This compartment was also characterized by a spatially restricted immune response with a selective accumulation of distinct macrophage types jointly interacting with neutrophils and stromal cells. This raised the possibility that local cell organization influences osteoclast precursor differentiation. We identified a distinct Spp1hi macrophage subset restricted to the cortex, which acted as a transitional precursor population giving rise to osteoclasts. Neutrophils preceded this Spp1hi macrophage accumulation and may promote their recruitment through chemotactic signaling. This coordination was less pronounced in aged mice despite preserved transcriptional states. In parallel, stromal cells in young animals displayed higher expression of essential niche factors further supporting local osteoclastogenesis at the cortex. Together, our findings identify distinct macrophage precursors and reveal early, cortex-specific niche activity supporting osteoclastogenesis. This provides a new framework for understanding the initiation of spatial immune-stromal interactions for the early stages of regeneration.

immunology↗