Biology subjects

Storer, M. A.

Publications and source records attributed to Storer, M. A..

2 recordsLinked to original sources

bioRxiv2024

Hyaluronic Acid and Emergent Tissue Mechanics Orchestrate Digit Tip Regeneration

Tissue regeneration is a dynamic process requiring coordinated cell fate decisions to restore structure and function. For instance, the tips of human and rodent digits fully regrow after amputation, although more proximal injuries fail to regenerate. While biochemical cues have been widely studied in wound healing, the role of the physical microenvironment remains less understood. Here, we discovered that tissue mechanics and extracellular matrix (ECM) composition differ markedly between non-regenerating and regenerating wounds. These differences are due to specific fibroblast sub-types which predominate in the non-regenerating wound and form fibrotic collagen networks. Conversely, bone-forming progenitors in regenerating digits synthesize abundant hyaluronic acid, which mediates collagen fibrillogenesis. By modeling the tissue mechanics of non-regenerative and regenerative wounds using hydrogels, we showed that substrate stiffness regulates the synthesis of fibrotic and regenerative ECM. We further revealed that mimicking the regenerative wound mechanics upregulated bone morphogenic protein signaling and osteogenic differentiation. We ultimately demonstrated that the link protein HAPLN1 promotes hyaluronic acid deposition in vivo, reduces scar formation, and induces bone repair after non-regenerative amputations. These findings emphasize the interplay among the ECM, tissue mechanics, and cell behavior in digit regeneration and point towards ECM modulation as a strategy to improve wound healing. HighlightsO_LINon-regenerating and regenerating digit tips diverge in their cellular and ECM composition C_LIO_LIRegeneration requires hyaluronic acid matrix, which mediates collagen assembly and tissue mechanics C_LIO_LISoft substrates enhance BMP signaling and propagate the synthesis of regenerative ECM C_LIO_LIHAPLN1 overexpression initiates rescue of non-regenerative digit tip amputations C_LI

developmental biology↗

bioRxiv2022

A human embryonic limb cell atlas resolved in space and time

Human limbs emerge during the fourth post-conception week as mesenchymal buds which develop into fully-formed limbs over the subsequent months. Limb development is orchestrated by numerous temporally and spatially restricted gene expression programmes, making congenital alterations in phenotype common. Decades of work with model organisms has outlined the fundamental processes underlying vertebrate limb development, but an in-depth characterisation of this process in humans has yet to be performed. Here we detail the development of the human embryonic limb across space and time, using both single-cell and spatial transcriptomics. We demonstrate extensive diversification of cells, progressing from a restricted number of multipotent progenitors to myriad mature cell states, and identify several novel cell populations, including neural fibroblasts and multiple distinct mesenchymal states. We uncover two waves of human muscle development, each characterised by different cell states regulated by separate gene expression programmes. We identify musculin (MSC) as a key transcriptional repressor maintaining muscle stem cell identity and validate this by performing MSC knock down in human embryonic myoblasts, which results in significant upregulation of late myogenic genes. Through integration of multiple anatomically continuous spatial transcriptomic samples, we spatially map single-cell clusters across a sagittal section of a whole fetal hindlimb. We reveal a clear anatomical segregation between genes linked to brachydactyly and polysyndactyly, and uncover transcriptionally and spatially distinct populations of mesenchyme in the autopod. Finally, we perform scRNA-seq on murine embryonic limbs to facilitate cross-species developmental comparison at single-cell resolution, finding substantial homology between the two species.

developmental biology↗