Biology subjects

Herriges, M.

Publications and source records attributed to Herriges, M..

4 recordsLinked to original sources

bioRxiv2026

The chromatin remodeling complex PRC2 safeguards cell fate in alveolar epithelial type 2 cells

Maintenance of the gas exchange surface throughout life and regeneration of the lung after injury requires tight regulation of epithelial cell fate and function. Alveolar epithelial type 2 (AT2) cells serve as the progenitors of the distal epithelium, differentiating into alveolar epithelial type 1 (AT1) cells or proliferating to maintain the quorum of AT2 cells. Here we describe the role of the chromatin regulator polycomb repressive complex 2 (PRC2) in the maintenance of AT2 cell fate in the adult alveolus. Cross-species single-cell transcriptomic analyses identified PRC2 activation in proliferative AT2 populations. PRC2 loss of function in human iPSC-derived AT2 (iAT2) cells and primary murine AT2 cells in vitro resulted in loss of AT2 cell state and emergence of programs reminiscent of alveolar-basal intermediate (ABI) cell states, while overexpression of the PRC2 enzymatic component EZH2 in human iAT2 cells augmented the AT2 cell program. Genetic loss of PRC2 function in the AT2 lineage in adult mice in vivo led to emphysematous remodeling of the lung and induced a time-dependent series of transitions of AT2 cells through an alveolar-basal intermediate (ABI) state into Krt5+ basal-like cells. Comparison of murine ABI cells to human disease-associated ABI cells demonstrates de-repression of canonical PRC2 targets during transition to ABI and basal-like states in human fibrosis, implicating PRC2 is a conserved regulator of AT2 cell fate. Together, these findings define PRC2 complex function during AT2 cell self-renewal as a critical guardrail for maintaining epithelial cell fate in the adult lung.

genetics↗

bioRxiv2023

scTOP: physics-inspired order parameters for cellular identification and visualization

Advances in single-cell RNA-sequencing (scRNA-seq) provide an unprecedented window into cellular identity. The increasing abundance of data requires new theoretical and computational frameworks for understanding cell fate determination, accurately classifying cell fates from expression data, and integrating knowledge from cell atlases. Here, we present single-cell Type Order Parameters (scTOP): a statistical-physics-inspired approach for constructing "order parameters" for cell fate given a reference basis of cell types. scTOP can quickly and accurately classify cells at a single-cell resolution, generate interpretable visualizations of developmental trajectories, and assess the fidelity of engineered cells. Importantly, scTOP does this without using feature selection, statistical fitting, or dimensional reduction (e.g., UMAP, PCA, etc.). We illustrate the power of scTOP utilizing a wide variety of human and mouse datasets (both in vivo and in vitro). By reanalyzing mouse lung alveolar development data, we characterize a transient perinatal hybrid alveolar type 1/alveolar type 2 (AT1/AT2) cell population that disappears by 15 days post-birth and show that it is transcriptionally distinct from previously identified adult AT2-to-AT1 transitional cell types. Visualizations of lineage tracing data on hematopoiesis using scTOP confirm that a single clone can give rise to as many as three distinct differentiated cell types. We also show how scTOP can quantitatively assess the transcriptional similarity between endogenous and transplanted cells in the context of murine pulmonary cell transplantation. Finally, we provide an easy-to-use Python implementation of scTOP. Our results suggest that physics-inspired order parameters can be an important tool for understanding development and characterizing engineered cells.

biophysics↗

bioRxiv2022

Durable alveolar engraftment of PSC-derived lung epithelial cells into immunocompetent mice

Durable reconstitution of the injured distal lung epithelium with pluripotent stem cell (PSC) derivatives, if realized, would represent a promising potential therapy for diseases that result from alveolar damage. Here we differentiate murine PSCs in vitro into self-renewing lung epithelial progenitors able to engraft into the injured distal lung epithelium of immunocompetent, syngeneic mouse recipients. Emulating the roadmap of the developing embryo, we generate transplantable PSC-derived Nkx2-1+/Sox9+ lung epithelial progenitors that are highly similar to cultured primary embryonic distal lung bud tip progenitors. These cells display a stable phenotype after frozen archiving or extensive expansion in culture, providing a nearly inexhaustible source of cells that can be engrafted into syngeneic injured mouse lungs without the need for immunosuppression. After transplantation PSC-derived tip-like progenitors downregulate Sox9 and mature in the distal lung, upregulating alveolar type 2 cell markers or assuming the flat morphology and molecular phenotype of terminally differentiated alveolar type 1 cells. After months in vivo, donor-derived cells retain their alveolar epithelial type 2-like and type 1-like phenotypes, as characterized by single cell RNA sequencing, ultrastructural analyses, in vivo histologic profiling, and ex vivo organoid assays that demonstrate continued capacity of the engrafted cells to proliferate and differentiate. These results indicate durable reconstitution of the distal lungs facultative progenitor and differentiated epithelial cell compartments in vivo with PSC-derived cells, thus establishing a novel model for pulmonary cell therapy which can be utilized to better understand the mechanisms and utility of engraftment prior to future clinical studies.

cell biology↗

bioRxiv2021

TBX5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development

The gene regulatory networks that coordinate the development of the cardiac and pulmonary systems are essential for terrestrial life but poorly understood. The T-box transcription factor Tbx5 is critical for both pulmonary specification and heart development, but how these activities are mechanistically integrated remains unclear. We show that Tbx5 regulates an evolutionarily conserved retinoic acid (RA)-Hedgehog-Wnt signaling cascade coordinating cardiopulmonary development. We demonstrate that Tbx5 directly maintains expression of the RA-synthesizing enzyme Aldh1a2 in the foregut lateral plate mesoderm via an intronic enhancer that is evolutionarily conserved among terrestrial vertebrates. Tbx5 promotes posterior second heart field identity in a positive feedback loop with RA, antagonizing a Fgf8-Cyp regulatory module and restricting FGF activity to the anterior. Tbx5/Aldh1a2-dependent RA signaling also directly activates Shh transcription in the adjacent foregut endoderm through the conserved MACS1 enhancer. Epithelial Hedgehog then signals back to the mesoderm, where together with Tbx5 it activates expression of Wnt2/2b that ultimately induce pulmonary fate in the foregut endoderm. These results provide mechanistic insight into the interrelationship between heart and lung development informing cardiopulmonary evolution and birth defects. KEY FINDINGSO_LITbx5 regulates second heart field patterning and pulmonary development via retinoic acid (RA) and Hedgehog (Hh) signaling. C_LIO_LITbx5 directly maintains transcription of the RA-synthesizing enzyme Aldh1a2 in the posterior second heart field mesoderm via an evolutionarily conserved intronic enhancer. C_LIO_LIDownstream of Tbx5, RA directly promotes Shh transcription through the evolutionarily conserved MACS1 endoderm enhancer. C_LIO_LIDownstream of Tbx5, RA suppresses FGF signaling to pattern the second heart field while promoting a Hedgehog-Wnt2/2b signaling cascade that induces pulmonary fate. C_LI SUMMARY STATEMENTTbx5-dependent Retinoic Acid signaling regulates an evolutionarily conserved gene regulatory network that coordinates cardiac and pulmonary development.

developmental biology↗