Heart and Brain Pericytes Exhibit a Pro-Fibrotic Response After Vascular Injury

Pham, Thanh Thuy Dan; Park, Shuin; Kolluri, Kamal; Kawaguchi, Riki; Wang, Lingjun; Tran, D.C.; Zhao, Peng; Carmichael, S. Thomas; Ardehali, Reza

doi:10.1161/circresaha.121.319288

Cited by 16 publications

(10 citation statements)

References 5 publications

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“…Our findings, however, clearly indicate a participation of PC-derived tdTomato + cells in fibrotic scar formation after ONC, constituting up to 90% of PDGFRβ + scar-forming cells in the lesion. In line with our findings, the contribution of PC (subpopulations) to scar formation was reported in inducible lineage tracing models following SCI (Glast promoter) ( Goritz et al, 2011 ) or vascular ischemia in the heart and brain (tbx18 promoter) ( Pham et al, 2021 ).…”

Section: Discussionsupporting

confidence: 91%

“…Applying distinct promoters, the participation of PC (-subpopulations) in scar formation was confirmed after SCI using the inducible Glast-CreER transgenic mouse ( Goritz et al, 2011 ) and further in two kidney fibrosis models, using an inducible FoxD1-CreER T2 mouse ( Humphreys et al, 2010 ). Using the tbx18-CreER T2 lineage tracing model, Guimaraes-Camboa et al (2017) excluded in vivo trans-differentiation of PCs in different lesions, whereas Pham et al (2021) reported a pro-fibrotic response of heart and brain PCs after vascular injury in the same mouse model. Contradicting findings regarding the endogenous trans-differentiation potential of PCs may result from differences in the severity of the applied injury models (e.g., small versus large cortico-striatial stab lesion), as demonstrated by Dias et al (2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, findings are inconsistent, as the definition and characterization of PCs are not uniform across studies and several constitutive and inducible transgenic mouse models have been used to study PC trans-differentiation capacity. Importantly, fibrosis in CNS and the participation of PCs have been studied mainly in spinal cord or brain injury ( Goritz et al, 2011 ; Dias et al, 2021 ; Pham et al, 2021 ). The ONC injury mouse model is an important experimental model to mimic and study human diseases like traumatic optic neuropathy or ON degeneration in glaucoma.…”

Section: Introductionmentioning

confidence: 99%

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Pericyte-derived cells participate in optic nerve scar formation

et al. 2023

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Introduction: Pericytes (PCs) are specialized cells located abluminal of endothelial cells on capillaries, fulfilling numerous important functions. Their potential involvement in wound healing and scar formation is achieving increasing attention since years. Thus, many studies investigated the participation of PCs following brain and spinal cord (SC) injury, however, lacking in-depth analysis of lesioned optic nerve (ON) tissue. Further, due to the lack of a unique PC marker and uniform definition of PCs, contradicting results are published.Methods: In the present study the inducible PDGFRβ-P2A-CreERT2-tdTomato lineage tracing reporter mouse was used to investigate the participation and trans-differentiation of endogenous PC-derived cells in an ON crush (ONC) injury model, analyzing five different post lesion time points up to 8 weeks post lesion.Results: PC-specific labeling of the reporter was evaluated and confirmed in the unlesioned ON of the reporter mouse. After ONC, we detected PC-derived tdTomato+ cells in the lesion, whereof the majority is not associated with vascular structures. The number of PC-derived tdTomato+ cells within the lesion increased over time, accounting for 60–90% of all PDGFRβ+ cells in the lesion. The presence of PDGFRβ+tdTomato- cells in the ON scar suggests the existence of fibrotic cell subpopulations of different origins.Discussion: Our results clearly demonstrate the presence of non-vascular associated tdTomato+ cells in the lesion core, indicating the participation of PC-derived cells in fibrotic scar formation following ONC. Thus, these PC-derived cells represent promising target cells for therapeutic treatment strategies to modulate fibrotic scar formation to improve axonal regeneration.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pericyte-derived cells participate in optic nerve scar formation

et al. 2023

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“…Of interest, we have observed that pericytes differentially express fibrosis markers in mdxD2-NSG and mdx-NSG muscles such as Postn , Col1a1/a2 and Fn1 compared to wt-NSG(not shown). A similar pro-fibrotic signature of pericytes has been described in heart and brain after ischemic injury ( Pham et al., 2021 ). A common signaling pathway associated with both ischemia injury as well as dystrophic and severely dystrophic environments is exacerbated TGF-ꞵ signaling, which we speculate is resulting in a similar fibrotic signature in the pericytes in dystrophic and severely dystrophic muscles.…”

Section: Discussionsupporting

confidence: 68%

Single cell sequencing maps skeletal muscle cellular diversity as disease severity increases in dystrophic mouse models

Saleh¹,

Xi²,

Switzler³

et al. 2022

iScience

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“…We hypothesize that this cell type, along with FB1, may be related to valvular fibroblasts, but further studies are required to establish this potential relationship. Finally, we defined a cluster of pre-smooth muscle cells (preSMC) with MYH11 , PDGFRB , and TAGLN activity but lacking TCF21 activity (Dobnikar et al 2018), a cluster of smooth muscle cells (SMC) exhibiting stronger activity for MYH11 and PDGFRB with major contributions from PCW19 and minor contributions from PCW8, and a cluster of pericytes (PC) with activity of PDGFRB and ABCC9 ( Figure 1d, SFigure 3 ) (Pham et al 2021). We also defined a cluster of neural crest (NC) cells with high TFAP2A activity ( Figure 1d, SFigure 3 ) (W.-D. Wang et al 2011).…”

Section: Resultsmentioning

confidence: 99%

Integrative single-cell analysis of cardiogenesis identifies developmental trajectories and non-coding mutations in congenital heart disease

Ameen

Sundaram

Banerjee

et al. 2022

Preprint

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Congenital heart defects, the most common birth disorders, are the clinical manifestation of anomalies in fetal heart development - a complex process involving dynamic spatiotemporal coordination among various precursor cell lineages. This complexity underlies the incomplete understanding of the genetic architecture of congenital heart diseases (CHDs). To define the multi-cellular epigenomic and transcriptional landscape of cardiac cellular development, we generated single-cell chromatin accessibility maps of human fetal heart tissues. We identified eight major differentiation trajectories involving primary cardiac cell types, each associated with dynamic transcription factor (TF) activity signatures. We identified similarities and differences of regulatory landscapes of iPSC-derived cardiac cell types and their in vivo counterparts. We interpreted deep learning models that predict cell-type resolved, base-resolution chromatin accessibility profiles from DNA sequence to decipher underlying TF motif lexicons and infer the regulatory impact of non-coding variants. De novo mutations predicted to affect chromatin accessibility in arterial endothelium were enriched in CHD cases versus controls. We used CRISPR-based perturbations to validate an enhancer harboring a nominated regulatory CHD mutation, linking it to effects on the expression of a known CHD gene JARID2. Together, this work defines the cell-type resolved cis-regulatory sequence determinants of heart development and identifies disruption of cell type-specific regulatory elements as a component of the genetic etiology of CHD.

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Heart and Brain Pericytes Exhibit a Pro-Fibrotic Response After Vascular Injury

Cited by 16 publications

References 5 publications

Pericyte-derived cells participate in optic nerve scar formation

Pericyte-derived cells participate in optic nerve scar formation

Single cell sequencing maps skeletal muscle cellular diversity as disease severity increases in dystrophic mouse models

Integrative single-cell analysis of cardiogenesis identifies developmental trajectories and non-coding mutations in congenital heart disease

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