Biology subjects

Lim, A. A.

Publications and source records attributed to Lim, A. A..

3 recordsLinked to original sources

bioRxiv2025

Human pluripotent stem cell-derived atrioventricular node-like pacemaker cells exhibit biological conduction bridge properties in vitro and in vivo

The atrioventricular node (AVN) ensures synchronized heart contractions by establishing the electrical connection between the atria and ventricles. Dysfunction of the pacemaker cells of the AVN leads to atrioventricular block (AV block), a life-threatening condition managed with electronic pacemakers (EPMs). EPMs have drawbacks that could be overcome by a human pluripotent stem cell (hPSC)-derived biological conduction bridge (BioCB). Recent studies demonstrated the differentiation of AVN-like cells from hPSCs, but their conduction properties upon engraftment in vivo remain unexplored. Here we report the generation of AVN-like pacemaker cells (AVNLPCs) from hPSCs using WNT and BMP signaling modulation. These AVNLPCs transcriptionally resemble fetal AVN pacemaker cells, exhibit pacemaker action potentials, and display unique AVN-like conduction properties. Notably, when transplanted into the guinea pig heart, AVNLPCs replicate the functional properties of the AVN. Our study highlights the potential of an AVNLPC-based BioCB as novel cell therapy to improve treatment for AV block patients.

developmental biology↗

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↗

bioRxiv2020

Comparison of human and mouse fetal intestinal tissues reveals differential maturation timelines.

Maturation of the intestinal epithelium is a necessary step for development of a fully functioning gastrointestinal tract. Studies of rodent gastrointestinal development and maturation have long been used to guide understanding of human intestinal maturation, in part because accessing human gestational stage intestinal tissues to perform equivalent human studies can be difficult. Notable differences have already been described in the timing of key stages in intestinal development between rodents and humans, but the conservation of intestinal maturation events between the two species is poorly understood. We hypothesized that species-related differences in intestinal development would alter the timing of key maturation events between human and mouse. We tested our hypothesis by performing a detailed comparison of hallmarks of intestinal maturation in human and mouse gestational intestine, including markers that describe the emergence of intestinal cell types, functionality and structural integrity. Our study demonstrates clear timing differences between maturation stages in mouse and human, with the majority of human maturation hallmarks acquired post-partum, in contrast to their gestational emergence in mouse. Our work suggests caution when translating murine intestinal maturation observations to the human, and provides a maturation road map that will be helpful to those seeking to produce mature intestine from in vitro stem cell sources.

developmental biology↗