Functional heterogeneity of cell populations increases robustness of pacemaker function in a numerical model of the sinoatrial node tissue

Each heartbeat is initiated by specialized pacemaker cells operating within the sinoatrial node (SAN). While individual cells within SAN tissue exhibit substantial heterogeneity of their electrophysiological parameters and Ca cycling, the role of this heterogeneity for cardiac pacemaker function remains mainly unknown. Here we investigated the problem numerically in a 25x25 square grid of coupled-clock Maltsev-Lakatta cell models and tested the hypothesis that functional heterogeneity of cell populations increases robustness of SAN function. The tissue models were populated by cells with different degree of heterogeneity of the two key model parameters of the coupled-clock system, maximum L-type Ca current conductance (gCaL) and sarcoplasmic reticulum Ca pumping rate (Pup). Our simulations showed that in the areas of Pup-gCaL parametric space at the edge of the system stability where action potential (AP) firing was absent or dysrhythmic in tissues populated by identical cells, rhythmic AP generation was rescued in tissues populated by cells with uniformly random distributions of gCaL or Pup (but keeping the same average values). This effect to increase robust AP generation was synergistic with respect to heterogeneity in both gCaL and Pup and was further strengthened by clustering of cells with higher gCaL or Pup. The effect of functional heterogeneity was not due to a simple summation of activity of intrinsically firing cells naturally present in SAN; rather AP firing cells locally and critically interacted with non-firing/dormant cells. When firing cells prevailed, they recruited many dormant cells to fire, strongly enhancing overall SAN function. And vice versa, prevailing dormant cells suppressed AP firing in cells with intrinsic automaticity and halted SAN automaticity.

Advances in single-cell multi-omics profiling

Single-cell multi-omics profiling methods are developed to dissect heterogeneity of cell populations.

Single-cell transcriptomic analysis identifies extensive heterogeneity in the cellular composition of mouse Achilles tendons

Tendon is a dense connective tissue that stores and transmits forces between muscles and bones. Cellular heterogeneity is increasingly recognized as an important factor in the biological basis of tissue homeostasis and disease, yet little is known about the diversity of cell types that populate tendon. To address this, we determined the heterogeneity of cell populations within mouse Achilles tendons using single-cell RNA sequencing. In assembling a transcriptomic atlas of Achilles tendons, we identified 11 distinct types of cells, including three previously undescribed populations of tendon fibroblasts. Prior studies have indicated that pericytes, which are found in the vasculature of tendons, could serve as a potential source of progenitor cells for adult tendon fibroblasts. Using trajectory inference analysis, we provide additional support for the notion that pericytes are likely to be at least one of the progenitor cell populations for the fibroblasts that compose adult tendons. We also modeled cell-cell interactions and identified previously undescribed ligand-receptor signaling interactions involved in tendon homeostasis. Our novel and interactive tendon atlas highlights previously underappreciated heterogeneity between and within tendon cell populations. The atlas also serves as a resource to further the understanding of tendon extracellular matrix assembly and maintenance and in the design of therapies for tendinopathies.

Cell types diversity of H4 haplotype Placozoa sp.

Placozoa is one of the five basal metazoan lineages critical for our understanding of animal evolution in general, and the origin of neuromuscular organization in particular. All Placozoa have the simplest known animal body plan, without neurons and muscles, but relatively complex behaviors. Totally 19 haplotypes of placozoans have been identified including two genera, Trichoplax adhaerens (H1) and Hoilungia hongkongensis (H13), plus a number of less characterized ecological groups also known as H2–H19 Placozoa sp. However, microscopic anatomy had been characterized for H1 (Trichoplax adhaerens) only. Here, using scanning and confocal microscopy, we described morphological organization of H4, the haplotype similar to Hoilungia. All six basal morphological cell types have been found in H4. Nevertheless, we recognized a greater heterogeneity of cell populations (in their shape, density, mitochondrial distribution and activity) than described elsewhere for H1. This study expands our knowledge about the biology of these enigmatic groups of marine organisms.

Morphologic Heterogeneity of Cell Populations Isolated by Density Gradient Centrifugation from Serous Fluids of Ovarian Tumors

The cells of tumor fluid from patients with malignant and benign serous ovarian neoplasms were fractionated using Ficoll-Uropoline density gradient centrifugation. Density distribution and morphologic characteristics of cell fractions were analyzed. It was found that serous ovarian adenocarcinomas contained three to four types of morphologically malignant cells focused in low density layers. Borderline ovarian neoplasms showed the presence of one subpopulation of cells with some features of malignancy and cells with some atypical but non-malignant features. The fluids of serous cysts contained mainly normal epithelial cells representing different stages of morphological maturity and were focused in denser layers. The results allowed us to catalogue ovarian tumor cell subpopulations present in each density fraction of individual patients and confirmed that ovarian tumors could be diagnosed by morphologic identification of cells from tumor fluids.