Laboratory for Stem Cell Niches and Extrinsic Signaling

Our lab aims to establish causal, in vivo mechanisms by which microenvironmental (niche) cues regulate adult stem/progenitor cells. We focus on extracellular signals and tissue-level context, and we prioritize quantitative and functional tests over correlative observations.

Across these themes, we start from in vivo biology and seek generalizable, physiologically meaningful rules prioritizing causal mechanisms and quantitative readouts over correlative descriptions.

Neural fibers interwoven with niche stromal cells highlight neuro–microenvironment coupling as a key determinant of hematopoietic regeneration.

Microenvironmental control of regeneration

We study how neural inputs shape stem cell microenvironments and regenerative outcomes. In Gao et al., we demonstrated that leptin receptor–positive (LEPR ) stromal cells promote bone marrow innervation and regeneration by producing nerve growth factor, highlighting a stromal-to-nerve program embedded within the adult niche (Nat Cell Biol 25:1746). We extended this concept to a clinically relevant setting by showing that nonselective β-adrenergic receptor inhibitors impair hematopoietic regeneration after hematopoietic cell transplantation in mice and humans, underscoring the functional importance of adrenergic signaling during recovery (Cancer Discov 15:748). Building on these foundations, we are investigating how neural activity remodels marrow adipose and stromal compartments and how these changes influence HSC resilience and regeneration. More broadly, we test whether conserved neuro–microenvironment principles operate across tissues, aiming to convert nervous system effects into mechanistic, falsifiable models with physiologically meaningful readouts.

Growth factors and ECM as instructive niche cues

We view the extracellular matrix (ECM) not as a passive scaffold, but as an information-rich niche compartment that can encode growth-factor-like activities. Building on work defining Osteolectin/Clec11a as an osteogenic niche cue and identifying its receptor (eLife 5:e18782, eLife 8:e42274), we are interested in discovering additional ECM-associated molecules that instruct adult stem/progenitor behavior and produce clear physiological outputs, such as longitudinal bone growth, skeletal maintenance and regeneration. A parallel focus is understanding how these cues are regulated, i.e., how their abundance, activation, and spatial presentation are tuned by systemic states and by remodeling of matrix architecture, so that “signal availability” becomes a testable, in vivo mechanism rather than a descriptive concept. To connect niche remodeling to rare progenitors in situ, we integrate lineage tracing with deep-tissue imaging and optical clearing of bone and marrow, enabling 3D visualization of stromal networks and their responses at cellular resolution (Bone Res 13:6). Our goal is to move from biology-driven observations to principled, causal rules for how ECM-encoded signals shape adult stem cell function.

MicroCT analysis showing accelerated bone loss during adulthood in mice with conditional deletion of integrin a11, a receptor for an osteogenic growth factor Osteolectin (eLife 8:e42274).

Mechanistic and quantitative in vivo interrogation

We prioritize causal, in vivo tests of niche mechanisms, combining functional assays with quantitative readouts.

Mechanical forces are a pervasive but often under-parameterized dimension of adult stem cell regulation. In our previous study (Nature 591:438), we identified a mechanosensitive peri-arteriolar niche that supports osteogenesis and lymphopoiesis, linking vascular microanatomy, mechanosensation, and stem/progenitor maintenance in vivo. Building on this framework, we are dissecting how mechanosensors in niche cells and force-dependent remodeling of fibronectin-rich matrices tune niche composition, signal presentation, and stem/progenitor behavior during homeostasis and regeneration. We also extend these mechanobiology principles beyond the bone marrow—for example to intestinal niches—to test what is conserved versus context-specific across organs. Across projects, we emphasize causal in vivo experiments paired with quantitative, organism-level endpoints, with the goal of establishing general rules for how mechanics intersects with extracellular signaling to control adult stem cell function.

A mechanosensitive niche model illustrates how vascular microanatomy and mechanical inputs can be translated into causal rules for adult stem cell regulation in vivo (Saçma & Geiger, Nature news & views).