Biology subjects

Weinstein, E.

Publications and source records attributed to Weinstein, E..

3 recordsLinked to original sources

bioRxiv2026

Scarless regeneration requires post-translational proteolytic regulation via macrophage-derived Legumain

Macrophages express proteolytic factors in response to injury but how proteases are deployed and regulated during regeneration are incompletely defined. Beyond their transcriptomic expression, activity of individual proteases is defined both by their unique substrate specificity and post-translational modifications of their active forms. Here we show a key role for the lysosomal protease Legumain in controlling ECM dynamics and post-translational processing of the regenerative proteome. Injury interface-targeted Ctsla localization and post-translational processing requires Lgmn in macrophages. Extracellular cues from physical remodeling control differentiation state and injury response of ligament resident fibroblasts. Loss of ECM turnover, including localized Fibronectin 1a/b remodeling, impairs dedifferentiation in legumain mutants and leads to fibrotic scarring. Taken together, we demonstrate a role for macrophage-derived lysosomal proteases as specialized tools required to fine-tune proteome composition and function in regeneration.

cell biology↗

bioRxiv2024

Dynamic cell fate plasticity and tissue integration drive functional synovial joint regeneration

Adult mammalian synovial joints have limited regenerative capacity, where injuries heal with mechanically inferior fibrotic tissues. Here we developed a unilateral whole-joint resection model in adult zebrafish to advance our understanding of how to stimulate regrowth of native synovial joint tissues. Using a combination of microCT, histological, live imaging, and single-cell RNA sequencing (scRNAseq) approaches after complete removal of all joint tissues, we find de novo regeneration of articular cartilage, ligament, and synovium into a functional joint. Clonal lineage tracing and scRNAseq implicate a multipotent, neural crest-derived population in the adult skeleton as a cell source for these regenerating tissues. Together, our findings reveal latent molecular and cellular programs within the adult skeleton that are deployed to regenerate a complex joint with lubricated articular cartilage.

developmental biology↗

bioRxiv2020

Reading frame restoration at the EYS locus, and allele-specific chromosome removal after Cas9 cleavage in human embryos

The correction of disease-causing mutations in human embryos could reduce the burden of inherited genetic disorders in the fetus and newborn, and improve the efficiency of fertility treatments for couples with disease-causing mutations in lieu of embryo selection. Here we evaluate the repair outcomes of a Cas9-induced double-strand break (DSB) introduced on the paternal chromosome at the EYS locus, which carries a frame-shift mutation causing blindness. We show that the most common repair outcome is microhomology-mediated end joining, which occurs during the first cell cycle in the zygote, leading to embryos with non-mosaic restoration of the reading frame. However, about half of the breaks remain unrepaired, resulting in an undetectable paternal allele and, upon entry into mitosis, loss of one or both chromosomal arms. Thus, Cas9 allows for the modification of chromosomal content in human embryos in a targeted manner, which may be useful for the prevention of trisomies. HighlightsO_LICas9-mediated DSB induction and repair by end joining occurs within hours C_LIO_LIEnd joining provides an efficient way to restore reading frames without mosaicism C_LIO_LIUnrepaired DSBs persist through mitosis and result in frequent chromosome loss C_LI

genetics↗