Search

Ischemic cardiomyopathy (ICM) is the leading cause of heart failure worldwide, yet the cellular and molecular signature of this disease is largely unclear. Using single-nucleus RNA sequencing (snRNA-seq) and integrated computational analyses, we profile the transcriptomes of over 99,000 human cardiac nuclei from the non-infarct region of the left ventricle of 7 ICM transplant recipients and 8 non-failing (NF) controls. We find the cellular composition of the ischemic heart is significantly altered, with decreased cardiomyocytes and increased proportions of lymphatic, angiogenic, and arterial endothelial cells in patients with ICM. We show that there is increased LAMININ signaling from endothelial cells to other cell types in ICM compared with NF. Finally, we find that the transcriptional changes that occur in ICM are similar to those in hypertrophic and dilated cardiomyopathies and that the mining of these combined datasets can identify druggable genes that could be used to target end-stage heart failure., Competing Interests: Declaration of interests C.A.K. is an employee of Bayer US LLC (a subsidiary of Bayer AG) and may own stock in Bayer. S.H., S.B., and C.A.K. were full-time employees of Bayer when this work was performed. P.T.E. has received sponsored research support from Bayer AG, IBM Health, Bristol Myers Squibb, and Pfizer; he has also served on advisory boards or consulted for Bayer AG, MyoKardia, and Novartis. K.B.M. has research grant funding from Amgen, USA and has also served on advisory boards for MyoKardia, Bristol-Myers Squibb, and Pfizer., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Histone variants contribute to the complexity of the chromatin landscape and play an integral role in defining DNA domains and regulating gene expression. The histone H3 variant H3.3 is incorporated into genic elements independent of DNA replication by its chaperone HIRA. Here we demonstrate that Hira is required for the self-renewal of adult hematopoietic stem cells (HSCs) and to restrain erythroid differentiation. Deletion of Hira led to rapid depletion of HSCs while differentiated hematopoietic cells remained largely unaffected. Depletion of HSCs after Hira deletion was accompanied by increased expression of bivalent and erythroid genes, which was exacerbated upon cell division and paralleled increased erythroid differentiation. Assessing H3.3 occupancy identified a subset of polycomb-repressed chromatin in HSCs that depends on HIRA to maintain the inaccessible, H3.3-occupied state for gene repression. HIRA-dependent H3.3 incorporation thus defines distinct repressive chromatin that represses erythroid differentiation of HSCs., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In response to retinal damage, the Müller glial cells (MGs) of the zebrafish retina have the ability to undergo a cellular reprogramming event in which they enter the cell cycle and divide asymmetrically, thereby producing multipotent retinal progenitors capable of regenerating lost retinal neurons. However, mammalian MGs do not exhibit such a proliferative and regenerative ability. Here, we identify Hippo pathway-mediated repression of the transcription cofactor YAP as a core regulatory mechanism that normally blocks mammalian MG proliferation and cellular reprogramming. MG-specific deletion of Hippo pathway components Lats1 and Lats2, as well as transgenic expression of a Hippo non-responsive form of YAP (YAP5SA), resulted in dramatic Cyclin D1 upregulation, loss of adult MG identity, and attainment of a highly proliferative, progenitor-like cellular state. Our results reveal that mammalian MGs may have latent regenerative capacity that can be stimulated by repressing Hippo signaling., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Specialized adult somatic cells, such as cardiomyocytes (CMs), are highly differentiated with poor renewal capacity, an integral reason underlying organ failure in disease and aging. Among the least renewable cells in the human body, CMs renew approximately 1% annually. Consistent with poor CM turnover, heart failure is the leading cause of death. Here, we show that an active version of the Hippo pathway effector YAP, termed YAP5SA, partially reprograms adult mouse CMs to a more fetal and proliferative state. One week after induction, 19% of CMs that enter S-phase do so twice, CM number increases by 40%, and YAP5SA lineage CMs couple to pre-existing CMs. Genomic studies showed that YAP5SA increases chromatin accessibility and expression of fetal genes, partially reprogramming long-lived somatic cells in vivo to a primitive, fetal-like, and proliferative state., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cellular heterogeneity within the mammalian brain poses a challenge toward understanding its complex functions. Within the olfactory bulb, odor information is processed by subtypes of inhibitory interneurons whose heterogeneity and functionality are influenced by ongoing adult neurogenesis. To investigate this cellular heterogeneity and better understand adult-born neuron development, we utilized single-cell RNA sequencing and computational modeling to reveal diverse and transcriptionally distinct neuronal and nonneuronal cell types. We also analyzed molecular changes during adult-born interneuron maturation and uncovered developmental programs within their gene expression profiles. Finally, we identified that distinct neuronal subtypes are differentially affected by sensory experience. Together, these data provide a transcriptome-based foundation for investigating subtype-specific neuronal function in the olfactory bulb (OB), charting the molecular profiles that arise during the maturation and integration of adult-born neurons and how they dynamically change in an activity-dependent manner., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

During development, progenitors progress through transition states. The cardiac epicardium contains progenitors of essential non-cardiomyocytes. The Hippo pathway, a kinase cascade that inhibits the Yap transcriptional co-factor, controls organ size in developing hearts. Here, we investigated Hippo kinases Lats1 and Lats2 in epicardial diversification. Epicardial-specific deletion of Lats1/2 was embryonic lethal, and mutant embryos had defective coronary vasculature remodeling. Single-cell RNA sequencing revealed that Lats1/2 mutant cells failed to activate fibroblast differentiation but remained in an intermediate cell state with both epicardial and fibroblast characteristics. Lats1/2 mutant cells displayed an arrested developmental trajectory with persistence of epicardial markers and expanded expression of Yap targets Dhrs3, an inhibitor of retinoic acid synthesis, and Dpp4, a protease that modulates extracellular matrix (ECM) composition. Genetic and pharmacologic manipulation revealed that Yap inhibits fibroblast differentiation, prolonging a subepicardial-like cell state, and promotes expression of matricellular factors, such as Dpp4, that define ECM characteristics., (Copyright © 2018 Elsevier Inc. All rights reserved.)