Biology subjects

Ehrbar, M.

Publications and source records attributed to Ehrbar, M..

4 recordsLinked to original sources

bioRxiv2026

Growth factor-free synthetic matrices reveal intrinsic skeletal progenitor competence

Clinical translation of human skeletal progenitor cells has been limited by the inability to reliably predict their regenerative performance, as current characterization methods rely on phenotypic markers or instructive differentiation assays that obscure intrinsic cell function. Here we demonstrate that human skeletal progenitor competence can only be revealed within a precisely defined and growth factor-free synthetic microenvironment. By independently tuning matrix mechanics, degradability, adhesion, and cell density within a fully synthetic poly(ethylene glycol) hydrogel, we create a permissive niche that enables human bone marrow stromal cells (hBMSCs) to undergo spontaneous bone formation in vivo without osteoinductive supplementation. These exogenous growth factor-free conditions expose donor-specific differences in bone forming capacity that are otherwise masked. Strikingly, supplementation with even low concentrations of BMP-2 abolished inter-donor variability, directly demonstrating that osteoinductive factors override intrinsic progenitor competence. Single-cell transcriptomics, proteomic profiling, and longitudinal in vivo analyses converge to show that high performing donors are defined by chondrocyte-primed transcriptional states and coordinated extracellular matrix (ECM) remodeling programs that establish a pro-osteochondral niche and drive bone formation via endochondral ossification. In contrast, low performing donors fail to initiate this cascade despite comparable phenotypic profiles and proliferation rates. Together, these findings implicate matrix context as a critical regulator of stem cell competence. Within this permissive synthetic niche, intrinsic ECM remodeling capacity emerges as a defining feature of donor-specific osteogenic potential, one that remains invisible to conventional assays. These matrices thus provide a functional platform for prospective stratification of skeletal progenitor cells, with direct implications for donor selection in regenerative medicine. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/731042v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@6fa9ceorg.highwire.dtl.DTLVardef@f51dddorg.highwire.dtl.DTLVardef@7bb040org.highwire.dtl.DTLVardef@706a36_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

A three-dimensional ex vivo model recapitulates in vivo features and unravels increased drug resistance in childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) preferentially localizes in the bone marrow (BM) and displays recurrent patterns of medullary and extra-medullary involvement. Leukemic cells exploit their niche for propagation and survive selective pressure by chemotherapy in the BM microenvironment, suggesting the existence of protective mechanisms. Here, we established a three-dimensional (3D) BM mimic with human mesenchymal stromal cells and endothelial cells that resemble vasculature-like structures to explore the interdependence of leukemic cells with their microenvironment. This model recapitulates recurrent topologic differences between B-cell and T-cell precursor ALL, whereby B-ALL interacts more closely with the mesenchymal compartment. Migration versatility was found to be associated with subtype, consistent with increased motility observed in T-ALL in vivo. Single-cell RNA signatures revealed similarities to profiles from in vivo patient derived xenografts, suggesting relevant states ex vivo. Furthermore, enhanced migration, adherence and cell cycle heterogeneity was visualized in our co-culture model. Finally, drug response profiling experiments in this 3D system reproduced established response patterns and indicated that drug resistant leukemic subpopulations may be detected more faithfully compared to information from two-dimensional models.

cancer biology↗

bioRxiv2023

Modelling Osteoarthritis pathogenesis through Mechanical Loading in an Osteochondral Unit-on-Chip

A cure for osteoarthritis (OA), the most prevalent musculoskeletal disease, remains an unmet need. Investigating the molecular and cellular processes leading to OA is challenged by the absence of human models that capture the complex interplay among different tissues in the joint under pathophysiological mechanical loading. In this study, we have engineered an OsteoChondral Unit (OCU)-on-chip system where composite hyaline cartilage - mineralized osseous microtissue analogues are exposed to controlled, tissue-specific compression regimes akin to those of the OCU in vivo. Through single-cell transcriptomic analysis, we demonstrate the critical relevance of the mineralized layer in inducing chondrocyte subpopulations implicated in the progression of OA. Upon exposure to hyperphysiological loading, the OCU-on-chip captures early phenotypic traits of OA pathogenesis, comprising alterations of subchondral mineral content and acquisition of previously described OA genetic signatures. This system enabled to identify novel upstream drivers of OA metabolic changes, including mechanically induced ribosomal alterations, as well as associated molecular targets towards the development of disease-modifying OA therapies.

bioengineering↗

bioRxiv2021

Microarrayed human bone marrow organoids for modeling blood stem cell dynamics

In many leukemia patients, a poor prognosis is attributed either to the development of chemotherapy resistance by leukemic stem cells (LSCs) or to the inefficient engraftment of transplanted hematopoietic stem/progenitor cells (HSPCs) into the bone marrow (BM). Here, we build a 3D in vitro model system of bone marrow organoids (BMOs) that recapitulate several structural and cellular components of native BM. These organoids are formed in a high-throughput manner from the aggregation of endothelial and mesenchymal cells within hydrogel microwells. Accordingly, the mesenchymal compartment shows partial maintenance of its self-renewal and multilineage potential, while endothelial cells self-organize into an interconnected vessel-like network. Intriguingly, such a vascular compartment enhances the recruitment of HSPCs in a chemokine ligand/receptor-dependent manner, reminiscent of HSPC homing behavior in vivo. Additionally, we also model LSC migration and nesting in BMOs, thus highlighting the potential of this system as a well accessible and scalable preclinical model for candidate drug screening and patient-specific assays.

bioengineering↗