Microvascular Mural Cell Organotypic Heterogeneity and Functional Plasticity

Holm, Annegret; Heumann, Tina; Augustin, Hellmut G.

doi:10.1016/j.tcb.2017.12.002

Cited by 113 publications

(128 citation statements)

References 118 publications

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“…In this study, we verified the existence of αSMA-positive perivascular cells in retinal capillaries by performing snap fixation as previously studied [8]. When the samples were fixed with PFA, no αSMA-positive cells were detected in the capillaries, as previously reported [6,21]; however, snap fixation revealed αSMA positive capillary perivascular cells in all three layers, residing along the capillary similar to capillary pericytes [4,22,23] rather than wrapping around like arterial VSMC. Inhibition of F-actin depolymerization was favorable for αSMA detection in the retinal capillary.…”

Section: Discussionsupporting

confidence: 83%

Alpha-Smooth Muscle Actin-Positive Perivascular Cells in Diabetic Retina and Choroid

Kim

Choi

et al. 2020

IJMS

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Structural alterations of pericytes in microvessels are important features of diabetic retinopathy. Although capillary pericytes had been known not to have α-smooth muscle actin (αSMA), a recent study revealed that a specific fixation method enabled the visualization of αSMA along retinal capillaries. In this study, we applied snap-fixation in wild type and streptozotocin-induced diabetic mice to evaluate the differences in vascular smooth muscle cells of the retina and the choroid. Mice eyeballs were fixed in ice-cold methanol to prevent the depolymerization of filamentous actin. Snap-fixated retina showed αSMA expression in higher-order branches along the capillaries as well as the arterioles and venules, which were not detected by paraformaldehyde fixation. In contrast, most choriocapillaris, except those close to the arterioles, were not covered with αSMA-positive perivascular mural cells. Large choroidal vessels were covered with more αSMA-positive cells in the snap-fixated eyes. Diabetes induced less coverage of αSMA-positive perivascular mural cells overall, but they reached higher-order branches of the retinal capillaries, which was prominent in the aged mice. More αSMA-positive pericytes were observed in the choroid of diabetic mice, but the αSMA-positive expression reduced with aging. This study suggests the potential role of smooth muscle cells in the pathogenesis of age-related diabetic retinopathy and choroidopathy.

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Section: Discussionsupporting

confidence: 83%

Alpha-Smooth Muscle Actin-Positive Perivascular Cells in Diabetic Retina and Choroid

Kim

Choi

et al. 2020

IJMS

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“…vSMCs and pericytes are the most well-studied blood vessel associated cells and are classically defined by the expression of alpha smooth muscle actin (ACTA2) and platelet-derived growth factor receptor b (PDGFRb), respectively (20,21). Lineage tracing in mice and chick-quail chimeras demonstrate a heterogeneous developmental origin of mural cells (20–23).…”

Section: Introductionmentioning

confidence: 99%

Dual function of perivascular fibroblasts in vascular stabilization in zebrafish

Rajan

Roger

Kocha

et al. 2020

Preprint

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24Blood vessels are vital to sustain life in all vertebrates. While it is known that mural cells (pericytes 25 and smooth muscle cells) regulate vascular integrity, the contribution of other cell types to vascular 26 stabilization has been largely unexplored. Using zebrafish, we identified sclerotome-derived 27 perivascular fibroblasts as a novel population of blood vessel associated cells. In contrast to pericytes, 28 perivascular fibroblasts emerge early during development, express the extracellular matrix (ECM) 29 genes col1a2 and col5a1, and display distinct morphology and distribution. Time-lapse imaging 30 reveals that perivascular fibroblasts serve as pericyte precursors. Genetic ablation of perivascular 31 fibroblasts results in dysmorphic blood vessels with variable diameters. Strikingly, col5a1 mutants 32show spontaneous hemorrhage, and the penetrance of the phenotype is strongly enhanced by the 33 additional loss of col1a2. Together, our work reveals dual roles of perivascular fibroblasts in vascular 34 stabilization where they establish the ECM around nascent vessels and function as pericyte 35 progenitors. 36 3 AUTHOR SUMMARY 37 38 Blood vessels are essential to sustain life in humans. Defects in blood vessels can lead to serious 39 diseases, such as hemorrhage, tissue ischemia, and stroke. However, how blood vessel stability is 40 maintained by surrounding support cells is still poorly understood. Using the zebrafish model, we 41 identify a new population of blood vessel associated cells termed perivascular fibroblasts, which 42 originate from the sclerotome, an embryonic structure that is previously known to generate the 43 skeleton of the animal. Perivascular fibroblasts are distinct from pericytes, a known population of 44 blood vessel support cells. They become associated with blood vessels much earlier than pericytes 45 and express several collagen genes, encoding main components of the extracellular matrix. Loss of 46 perivascular fibroblasts or mutations in collagen genes result in fragile blood vessels prone to 47 53 54The vascular system is crucial to the survival of vertebrates. Blood vessels must rapidly expand 55 and contract in response to systemic cues, but also maintain the stability to withstand the stress of 56 blood flow. To maintain their integrity, blood vessels are supported by a highly specialized 57 perivascular architecture comprised of blood vessel associated cells and the surrounding extracellular 58 matrix (ECM) (1,2). Compromised vascular integrity can result in devastating human diseases, such 59 as aneurysms, vascular malformations, and hemorrhagic strokes (3-6). However, how blood vessels 60 are stabilized by different perivascular components is still poorly understood. 61The prevailing model is that vascular stability is maintained at three different levels: endothelial 62 cells, mural cells and the surrounding ECM (2). First, blood vessels are lined by endothelial cells. 63Adherens and tight junctions between endothelial cells provide the primary barrier to passage o...

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“…Compared with the others, the c19 cluster expressed higher levels of canonical pericyte markers including Pdgfrb , Cspg4 (NG2), Rgs5 , Des and Kcnj8 . 18,36 It also exhibited high expression of VSMC contractile markers, including Acta2 , Cnn1 and Myh11 , 28 reflecting a heterozygous microvascular mural population comprising both pericytes and mVSMCs. Our smFISH results ultimately validated the presence of CNCC-derived pericytes in the heart through the co-expression of tdTomato and Vtn (Figure 2F).…”

Section: Resultsmentioning

confidence: 99%

“…Microvascular mural cells, comprising microvascular pericytes and microvascular smooth muscle cells, have recently been recognized playing a critical role in cardiac vascular homeostasis and disease. 18 The plasticity of microvascular pericytes makes them promising cells for application in cardiac regenerative medicine. 17 Nevertheless, the phenotypes of microvascular mural cells are variable, and canonical markers such as Pdgfrb, Des and Cspg4 do not specifically label them, as also shown in our data (Figure 2E), thus impeding the identification of the source and role of this important but heterogeneous population of cells.…”

Section: Discussionmentioning

confidence: 99%

“…Mural cells include pericytes that discontinuously ensheath capillaries and microvascular smooth muscle cells (mVSMCs) that cover larger-caliber vessels of the microcirculation as well as their transitional cells. 17,18 Neural crest-derived mural cells have been identified in various organs, such as the brain, retina, head and thymus. 19,20 However, one previous study did not find any CNCC-derived mural cells in the heart ventricle at E14.5 using lineage tracing.…”

Section: Introductionmentioning

confidence: 99%

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Single-cell transcriptomic landscape of cardiac neural crest cell derivatives during embryonic and neonatal development

Liu

Chen

et al. 2019

Preprint

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22 Rationale: Cardiac neural crest cells (CNCCs) contribute greatly to cardiovascular 23 development. A thorough understanding of the cell lineages, transcriptomic states and 24 regulatory networks of CNCC derivatives during normal development is essential for 25 deciphering the pathogenesis of CNCC-associated congenital anomalies. However, the 26 transcriptomic landscape of CNCC derivatives during development has not yet been 27 examined at a single-cell resolution. 28 Objective: We sought to systematically characterize the cell lineages, define the 29 developmental chronology and elucidate the transcriptomic dynamics of CNCC 30 derivatives during embryonic and neonatal development. 31 Methods and Results: We performed single-cell transcriptomic sequencing of 34,131 32 CNCC-derived cells in mouse hearts from eight developmental stages between E10.5 33 and P7. Through single-cell analyses and single-molecule fluorescence in situ 34 hybridization, we confirmed the presence of CNCC-derived mural cells. Furthermore, 35we found the transition from CNCC-derived pericytes to microvascular smooth muscle 36 cells, and identified the genes that were significantly regulated during this transition 37 through pseudo-temporal analysis. CNCC-derived neurons first appeared at E10.5, 38 which was earlier than previously recognized. In addition, the CNCC derivatives 39 switched from a proliferative to a quiescent state with the progression of development. 40Gradual loss of the neural crest molecular signature with development was also 41 observed in the CNCC derivatives. Our data suggested that many CNCC-derivatives 42 had already committed or differentiated to a specific lineage when migrating to the heart. 43Finally, we characterized some previously unknown subpopulations of CNCC 44 derivatives during development. For example, we found that Penk+ cells, which were 45 mainly localized in outflow tract cushions, were all derived from CNCCs. 46 Conclusions:Our study provides novel insights into the cell lineages, molecular 47 signatures, developmental chronology and state change dynamics of CNCC derivatives 48 during embryonic and neonatal development. Our dataset constitutes a valuable 49 resource that will facilitate future efforts in exploring the role of CNCC derivatives in 50 development and disease. 51

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Microvascular Mural Cell Organotypic Heterogeneity and Functional Plasticity

Cited by 113 publications

References 118 publications

Alpha-Smooth Muscle Actin-Positive Perivascular Cells in Diabetic Retina and Choroid

Alpha-Smooth Muscle Actin-Positive Perivascular Cells in Diabetic Retina and Choroid

Dual function of perivascular fibroblasts in vascular stabilization in zebrafish

Single-cell transcriptomic landscape of cardiac neural crest cell derivatives during embryonic and neonatal development

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