Biology subjects

Stockholm, D.

Publications and source records attributed to Stockholm, D..

6 recordsLinked to original sources

bioRxiv2025

Targeting lysosomal damage is a new therapeutic perspective for Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD), a muscle degenerative disease affecting young boys, arises from the loss of dystrophin. Current gene therapy approaches aim to restore a shortened form of dystrophin (microdystrophin) via Adeno-Associated Vector (AAV) delivery, but clinical studies show limited efficacy, emphasizing the need for improved strategies such as combined therapies. In this study, we identified lysosomal perturbations in the myofibers of DMD patients and animal models, an overlooked mechanism of cellular damage in muscular dystrophies. These were notably marked by the upregulation and recruitment of Galectin-3, a known biomarker of lysosomal membrane permeabilization, to damaged lysosomes, alongside alterations in lysosome number, morphology, and activation of endolysosomal damage response. Importantly, microdystrophin therapy in Dmdmdx mice fails to fully correct these damages. However, combining it with trehalose, a lysosome-protective disaccharide, significantly improves outcome, enhancing muscle function, histology and transcriptome. These findings highlight lysosomal damage as a novel mechanism in DMD pathogenesis and suggest that combining trehalose with gene therapy could enhance therapeutic efficacy. TeaserLysosomal damage contributes to DMD pathology and is an interesting therapeutic target worth considering for current and future approaches.

physiology↗

bioRxiv2023

CXCR4 signaling strength regulates hematopoietic multipotent progenitor fate through extrinsic and intrinsic mechanisms

How cell-extrinsic niche-related and cell-intrinsic cues drive lineage specification of hematopoietic multipotent progenitors (MPPs) in the bone marrow (BM) is partly understood. We show that CXCR4 signaling strength regulates localization and fate of MPPs. In mice phenocopying the BM myeloid skewing of patients with WHIM Syndrome (WS), a rare immunodeficiency caused by gain-of-function CXCR4 mutations, enhanced mTOR signaling and overactive Oxphos metabolism were associated with myeloid rewiring of lymphoid-primed MPPs (or MPP4). Fate decision of MPP4 was also affected by molecular changes established at the MPP1 level. Mutant MPP4 displayed altered BM localization relative to peri-arteriolar structures, suggesting that extrinsic cues contribute to their myeloid skewing. Chronic treatment with CXCR4 antagonist AMD3100 or mTOR inhibitor Rapamycin rescued lymphoid capacities of mutant MPP4, demonstrating a pivotal role for the CXCR4-mTOR axis in regulating MPP4 fate. Our study thus provides mechanistic insights into how CXCR4 signaling regulates the lymphoid potential of MPPs.

cell biology↗

bioRxiv2022

Differentiation is accompanied by a progressive loss in transcriptional memory

Cell differentiation requires the integration of two opposite processes, a stabilizing cellular memory, especially at the transcriptional scale, and a burst of gene expression variability which follows the differentiation induction. Therefore, the actual capacity of a cell to undergo phenotypic change during a differentiation process relies upon a modification in this balance which favors change-inducing gene expression variability. However, there are no experimental data providing insight on how fast the transcriptomes of identical cells would diverge on the scale of the very first two cell divisions during the differentiation process. In order to quantitatively address this question, we developed different experimental methods to recover the transcriptomes of related cells, after one and two divisions, while preserving the information about their lineage at the scale of a single cell division. We analyzed the transcriptomes of related cells from two differentiation biological systems (human CD34+ cells and T2EC chicken primary erythrocytic progenitors) using two different single-cell transcriptomics technologies (sc-RT-qPCR and scRNA-seq). We identified that the gene transcription profiles of differentiating sister-cells are more similar to each-other than to those of non related cells of the same type, sharing the same environment and undergoing similar biological processes. More importantly, we observed greater discrepancies between differentiating sister-cells than between self-renewing sister-cells. Furthermore, a continuous increase in this divergence from first generation to second generation was observed when comparing differentiating cousin-cells to self renewing cousin-cells. Our results are in favor of a continuous and gradual erasure of transcriptional memory during the differentiation process.

cell biology↗

bioRxiv2022

Plasma cell maintenance and antibody secretion are under the control of Sec22b-mediated regulation of organelle dynamics

Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the SNARE Sec22b as a unique and critical regulator of plasma cell maintenance and function. In absence of Sec22b, plasma cells were barely detectable and serum antibody titres were dramatically reduced. Accordingly, Sec22b deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b is indispensable for efficient antibody secretion but also for plasma cell fitness through the regulation of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil a critical role for Sec22b-mediated regulation of plasma cell biology through the control of organelle dynamics.

immunology↗

bioRxiv2020

Selective silencing rather than targeted activation of gene expression underlies fate choice in human hematopoietic stem cells.

When human cord blood derived CD34+ cells are induced to differentiate in vitro, they undergo rapid and dynamic morphological and molecular transformations that are critical for fate commitment. Using ATAC-seq and single-cell RNA sequencing, we detected two phases in this process. In the first phase, we observed a rapid and global chromatin opening that makes most of the gene promoters in the genome accessible, followed by widespread upregulation of gene transcription and a concomitant increase in the cell-to-cell variability of gene expression. The second phase is marked by a slow chromatin closure and a subsequent overall downregulation of gene transcription and emergence of coherent expression profiles corresponding to distinct cell subpopulations. These observations are consistent with a model based on the spontaneous probabilistic organization of the cellular process of fate commitment.

cell biology↗

bioRxiv2017

Integrated time-lapse and single-cell transcription studies highlight the variable and dynamic nature of human hematopoietic cell fate commitment.

Individual cells take lineage commitment decisions in a way that is not necessarily uniform. We address this issue by characterizing transcriptional changes in cord blood derived CD34+ cells at the single-cell level and integrating data with cell division history and morphological changes determined by time-lapse microscopy. We show, that major transcriptional changes leading to a multilineage-primed gene expression state occur very rapidly during the first cell cycle. One of the two stable lineage-primed patterns emerges gradually in each cell with variable timing. Some cells reach a stable morphology and molecular phenotype by the end of the first cell cycle and transmit it clonally. Others fluctuate between the two phenotypes over several cell cycles. Our analysis highlights the dynamic nature and variable timing of cell fate commitment in hematopoietic cells, links the gene expression pattern to cell morphology and identifies a new category of cells with fluctuating phenotypic characteristics, demonstrating the complexity of the fate decision process, away from a simple binary switch between two options as it is usually envisioned.

cell biology↗