A single-cell transcriptomic inventory of murine smooth muscle cells

Muhl, Lars; Mocci, Giuseppe; Pietilä, Riikka; Liu, Jianping; He, Liqun; Genové, Guillem; Leptidis, Stefanos; Gustafsson, Sonja; Buyandelger, Byambajav; Raschperger, Elisabeth; Hansson, Emil M.; Björkegren, Johan; Vanlandewijck, Michael; Lendahl, Urban; Betsholtz, Christer

doi:10.1016/j.devcel.2022.09.015

Cited by 31 publications

(35 citation statements)

References 81 publications

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“…While morphological and functional differences in ECs have been long-noted, scRNAseq confirmed there is both inter- and intra-vessel heterogeneity in different tissue and organ microenvironments (reviewed in [ 307 ]). This heterogeneity is not restricted to ECs, as recent work has cataloged substantial heterogeneity in smooth muscle cells throughout the vascular tree [ 308 ]. Single cell transcriptomics has enabled the discovery of new vascular subtypes in a host of physiological and pathophysiological settings.…”

Section: New Concepts In the Field Of Angiogenesismentioning

confidence: 99%

Pathological angiogenesis: mechanisms and therapeutic strategies

Dudley

2023

Angiogenesis

149

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In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, and coalescent angiogenesis, as well as vessel co-option, vasculogenic mimicry and lymphangiogenesis, underlie the formation of new vasculature. In many pathological conditions, such as cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity and SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but are often done so without the normal feedback mechanisms that regulate the ordinary spatial and temporal patterns of blood vessel formation. Thus, pathological angiogenesis presents new challenges yet new opportunities for the design of vascular-directed therapies. Here, we provide an overview of recent insights into blood vessel development and highlight novel therapeutic strategies that promote or inhibit the process of angiogenesis to stabilize, reverse, or even halt disease progression. In our review, we will also explore several additional aspects (the angiogenic switch, hypoxia, angiocrine signals, endothelial plasticity, vessel normalization, and endothelial cell anergy) that operate in parallel to canonical angiogenesis mechanisms and speculate how these processes may also be targeted with anti-angiogenic or vascular-directed therapies.

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Section: New Concepts In the Field Of Angiogenesismentioning

confidence: 99%

Pathological angiogenesis: mechanisms and therapeutic strategies

Dudley

2023

Angiogenesis

149

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“…To specifically investigate the extent to which physiologically relevant cardiovascular SMC gene programs were activated in our cellular reprogramming system, we investigated the expression of a cluster of heart and aortic SMC genes identified by a single-cell RNA-seq analysis on mouse heart and aorta ( 47 ). Heatmap representations of the expression changes across our different conditions show that WT MYOCD robustly activates this SMC gene program in 10T1/2 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Coactivator condensation drives cardiovascular cell lineage specification

Gan,

Eppert,

De La Cruz

et al. 2024

Sci. Adv.

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During development, cells make switch-like decisions to activate new gene programs specifying cell lineage. The mechanisms underlying these decisive choices remain unclear. Here, we show that the cardiovascular transcriptional coactivator myocardin (MYOCD) activates cell identity genes by concentration-dependent and switch-like formation of transcriptional condensates. MYOCD forms such condensates and activates cell identity genes at critical concentration thresholds achieved during smooth muscle cell and cardiomyocyte differentiation. The carboxyl-terminal disordered region of MYOCD is necessary and sufficient for condensate formation. Disrupting this region’s ability to form condensates disrupts gene activation and smooth muscle cell reprogramming. Rescuing condensate formation by replacing this region with disordered regions from functionally unrelated proteins rescues gene activation and smooth muscle cell reprogramming. Our findings demonstrate that MYOCD condensate formation is required for gene activation during cardiovascular differentiation. We propose that the formation of transcriptional condensates at critical concentrations of cell type–specific regulators provides a molecular switch underlying the activation of key cell identity genes during development.

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“…Despite providing unprecedented insight into the heterogeneity of diverse vascular beds, broadly designed studies are limited in defining more subtle differences within a blood vessel. Analysis of several hundred aortic SMCs, among thousands of cells, identified differential gene expression along the aorta, e.g., Des in the proximal aorta and Prrx2 in the distal aorta, yet distinct cell clusters by embryological origin or aortic segment were not defined (22).…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous Cardiac- and Neural Crest-Derived Aortic Smooth Muscle Cells have Similar Transcriptional Changes after TGFβ Signaling Disruption

Ren,

Jiang,

Hassab

et al. 2024

Preprint

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Smooth muscle cells (SMCs) of cardiac and neural crest origin contribute to the developing proximal aorta and are linked to disease propensity in adults. We analyzed single-cell transcriptomes of SMCs from mature thoracic aortas in mice to determine basal states and changes after disrupting transforming growth factor-β (TGFβ) signaling necessary for aortic homeostasis. A minority of Myh11 lineage-marked SMCs differentially expressed genes suggestive of embryological origin. Additional analyses in Nkx2-5 and Wnt1 lineage-marked SMCs derived from cardiac and neural crest progenitors, respectively, showed both lineages contributed to a major common cluster and each lineage to a minor distinct cluster. Common cluster SMCs extended from root to arch, cardiac subset cluster SMCs from root to mid-ascending, while neural crest subset cluster SMCs were restricted to the arch. The neural crest subset cluster had greater expression of a subgroup of TGFβ-dependent genes suggesting specific responsiveness or skewed extracellular matrix synthesis. Nonetheless, deletion of TGFβ receptors in SMCs resulted in similar transcriptional changes among all clusters, primarily decreased extracellular matrix molecules and modulators of TGFβ signaling. Many embryological markers of murine aortic SMCs were not confirmed in adult human aortas. We conclude: (i) there are multiple subtypes of cardiac- and neural crest-derived SMCs with shared or distinctive transcriptional profiles, (ii) neural crest subset SMCs with increased expression of certain TGFβ-inducible genes are not spatially linked to the aortic root predisposed to aneurysms from aberrant TGFβ signaling, and (iii) loss of TGFβ responses after receptor deletion is uniform among SMCs of different embryological origins.

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A single-cell transcriptomic inventory of murine smooth muscle cells

Cited by 31 publications

References 81 publications

Pathological angiogenesis: mechanisms and therapeutic strategies

Pathological angiogenesis: mechanisms and therapeutic strategies

Coactivator condensation drives cardiovascular cell lineage specification

Heterogeneous Cardiac- and Neural Crest-Derived Aortic Smooth Muscle Cells have Similar Transcriptional Changes after TGFβ Signaling Disruption

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