Biology subjects

Chang, M. L.

Publications and source records attributed to Chang, M. L..

2 recordsLinked to original sources

bioRxiv2024

Single-cell transcriptome analysis reveals CD34 as a novel marker of human sinoatrial node pacemaker cardiomyocytes

The sinoatrial node (SAN) regulates the heart rate throughout life. Failure of this primary pacemaker results in life-threatening, slow heart rhythm. Despite its important function, the cellular and molecular composition of the human SAN is not completely resolved. Particularly, no cell surface marker to identify and isolate SAN pacemaker cells has been reported to date. Here we used single-nuclei/cell RNA sequencing of fetal and human pluripotent stem cell (hPSC)- derived SAN cells and show that the SAN consists of three subtypes of pacemaker cells, including Core SAN, SAN, and Transitional Cells. Our study identified a host of novel Core SAN markers including MYH11, BMP4, and the cell surface antigen CD34. We demonstrate that sorting for CD34+ cells from cardiac hPSC differentiations enriches for SAN cells with a functional pacemaker phenotype. This novel SAN pacemaker cell surface marker is highly valuable for future hPSC- based disease modelling, drug discovery, cell replacement therapies, as well as the delivery of therapeutics to SAN cells in vivo using antibody-drug conjugates.

cell biology↗

bioRxiv2024

Molecular Visualization of Neuronal TDP43 Pathology In Situ

Nuclear exclusion and cytoplasmic accumulation of the RNA-binding protein TDP43 are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite this, the origin and ultrastructure of cytosolic TDP43 deposits remain unknown. Accumulating evidence suggests that abnormal RNA homeostasis can drive pathological TDP43 mislocalization, thereby enhancing RNA misprocessing due to the loss of nuclear TDP43, and engendering a cycle that ultimately leads to cell death. Here, we demonstrate that the addition of small monovalent oligonucleotides successfully recapitulates pathological TDP43 mislocalization and aggregation, aberrant splicing, and degeneration in iPSC-derived neurons (iNeurons). By employing a tailored multimodal in situ cryo-correlative light and electron microscopy pipeline, we examine the localization and aggregation of TDP43 in near-native conditions. We discover that mislocalized TDP43 accumulates and forms ordered fibrils within autophagosomes and lysosomes in iNeurons, as well as in ALS/FTLD patient tissue. We provide the first high-resolution snapshots of TDP43 aggregates in situ, delivering an unprecedented view of the earliest pathogenic events underlying ALS, FTLD, and related TDP43 proteinopathies.

neuroscience↗