Spatial transcriptomics reveal markers of histopathological changes in Duchenne muscular dystrophy mouse models

Nature Communications, vol. 14, pp. 4909

Abstract

Duchenne muscular dystrophy is caused by mutations in the DMD gene, leading to lack of dystrophin. Chronic muscle damage eventually leads to histological alterations in skeletal muscles. The identification of genes and cell types driving tissue remodeling is a key step to developing effective therapies. Here we use spatial transcriptomics in two Duchenne muscular dystrophy mouse models differing in disease severity to identify gene expression signatures underlying skeletal muscle pathology and to directly link gene expression to muscle histology. We perform deconvolution analysis to identify cell types contributing to histological alterations. We show increased expression of specific genes in areas of muscle regeneration (Myl4, Sparc, Hspg2), fibrosis (Vim, Fn1, Thbs4) and calcification (Bgn, Ctsk, Spp1). These findings are confirmed by smFISH. Finally, we use differentiation dynamic analysis in the D2-mdx muscle to identify muscle fibers in the present state that are predicted to become affected in the future state.

Authors 6

1. Laura G.M. Heezen Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

2. Tamim Abdelaal Aachen Department of Radiology, Leiden University Medical Center

   Leiden University Medical Center · Delft University of Technology · Cairo University

   Affiliation as printed

   Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands

   Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

   Systems and Biomedical Engineering Department, Faculty of Engineering Cairo University, Giza, Egypt

3. Maaike van Putten Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

4. Annemieke M Aartsma-Rus Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

5. Ahmed Essam Mahfouz Aachen Department of Human Genetics Leiden Computational Biology Center

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

   Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands

6. Pietro Spitali corresponding Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. p.spitali@lumc.nl

   Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands