Novel Blood Vascular Endothelial Subtype-Specific Markers in Human Skin Unearthed by Single-Cell Transcriptomic Profiling

He, Yuliang; Tacconi, Carlotta; Kim, Jihye; Restivo, Gaetana; Gousopoulos, Epameinondas; Lindenblatt, Nicole; Levesque, Mitchell P.; Claassen, Manfred; Detmar, Michael

doi:10.3390/cells11071111

Cited by 14 publications

(18 citation statements)

References 73 publications

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“…Nevertheless, besides the EPC cluster C7, we characterized 7 distinct EC signatures expressing gradually overlapping markers for arterioles (C1, C2), capillaries (C3, C4, C9), and postcapillary venules (C5, C6). This is in line with scRNAseq data from dermal ECs identifying 5 clusters (arterioles, capillary 1, capillary 2, postcapillary venules, venules) 71 , and 6 clusters (arterioles, post-arterial capillaries, prevenular capillaries, postcapillary venules, venules, collecting venules) 72 .…”

Section: Discussionsupporting

confidence: 88%

CD31 defines a subpopulation of human adipose-derived regenerative cells with potent angiogenic effects

Dhumale

Nielsen

Hansen

et al. 2023

Preprint

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Cellular heterogeneity represents a major challenge for regenerative treatment using freshly isolated Adipose Derived Regenerative Cells (ADRCs). Emerging data suggest superior efficacy of ADRCs as compared to the ex vivo expanded and more homogeneous ADRCs (=ASCs) for indications involving (micro)vascular deficiency, however, it remains unknown which ADRC cell subtypes account for the improvement. Surprisingly, we found regarding erectile dysfunction (ED) that the number of injected CD31+ ADRCs correlated positively with erectile function 12 months after one bolus of autologous ADRCs. Comprehensive in vitro and ex vivo analyses confirmed superior pro-angiogenic and paracrine effects of human CD31+ enriched ADRCs compared to the corresponding CD31- and parent ADRCs. When CD31+, CD31- and ADRCs were co-cultured in aortic ring- and corpus cavernous tube formation assays, the CD31+ ADRCs induced significantly higher tube development. This effect was corroborated using conditioned medium (CM), while quantitative mass spectrometric analysis suggested that this is likely explained by secretory pro-angiogenic proteins including DKK3, ANGPT2, ANAX2 and VIM, all enriched in CD31+ADRC CM. Single-cell RNA sequencing showed that transcripts of the upregulated and secreted proteins were present in 9 endothelial ADRC subsets including endothelial progenitor cells in the heterogenous non-cultured ADRCs. Our data suggest that the vascular benefit of using ADRCs in regenerative medicine is dictated by CD31+ ADRCs.

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Section: Discussionsupporting

confidence: 88%

CD31 defines a subpopulation of human adipose-derived regenerative cells with potent angiogenic effects

Dhumale

Nielsen

Hansen

et al. 2023

Preprint

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“…It is also known that miR-709 silences EGR2 by binding to the 3′UTR and the promoter region of EGR2 32 . Meanwhile, EGR2 is expressed in venular endothelial cells, but not in the endothelial cells of arterioles and post-arterial capillaries, based on an analysis of single-cell transcriptomic profiling for human dermal blood endothelial cells 33 . These suggest that miR-709 is expressed in arterial, but not in venous, endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

miR-709 exerts an angiogenic effect through a FGF2 upregulation induced by a GSK3B downregulation

Ueno,

Kurazumi,

Suzuki

et al. 2024

Sci Rep

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The aim of this study was to identify angiogenic microRNAs (miRNAs) that could be used in the treatment of hindlimb ischemic tissues. miRNAs contained in extracellular vesicles (EVs) deriving from the plasma were analyzed in C57BL/6 mice, which have ischemia tolerance, and in BALB/c mice without ischemia tolerance as part of a hindlimb ischemia model; as a result 43 angiogenic miRNA candidates were identified. An aortic ring assay was employed by using femoral arteries isolated from BALC/c mice and EVs containing miRNA; as a result, the angiogenic miRNA candidates were limited to 14. The blood flow recovery was assessed after injecting EVs containing miRNA into BALB/c mice with hindlimb ischemia, and miR-709 was identified as a promising angiogenic miRNA. miR-709-encapsulating EVs were found to increase the expression levels of the fibroblast growth factor 2 (FGF2) mRNA in the thigh tissues of hindlimb ischemia model BALB/c mice. miR-709 was also found to bind to the 3′UTR of glycogen synthase kinase 3 beta (GSK3B) in three places. GSK3B-knockdown human artery-derived endothelial cells were found to express high levels of FGF2, and were characterized by increased cell proliferation. These findings indicate that miR-709 induces an upregulation of FGF2 through the downregulation of GSK3B.

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“…4b). Furthermore, almost all endothelial cells in the skin organoid only expressed markers of capillary arterioles over the developmental time course [125][126][127] (Fig. 4b, Extended Data Fig.…”

Section: Macrophages Support Prenatal Skin Angiogenesismentioning

confidence: 99%

“…For endothelial cell modules, gene sets defining tip, stalk, arteriole, venule, lymphatic, capillary and hypoxia scores (Extended data Fig. 9g, h) were derived from published literature [125][126][127] . The list of genes for each gene module is provided in Supplementary Tables 18, 20.…”

Section: Gene Module Scoringmentioning

confidence: 99%

A human prenatal skin cell atlas reveals immune cell regulation of skin morphogenesis

Gopee,

Huang,

Olabi

et al. 2023

Preprint

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Human prenatal skin is populated by innate immune cells including macrophages, and whether they act solely in immunity or have additional functions in morphogenesis is unclear. We assembled the first comprehensive multi-omic reference atlas of prenatal human skin (7-16 post-conception weeks), combining single cell and spatial transcriptomic data, to characterise the skin's microenvironmental cellular organisation. This revealed that crosstalk between non-immune and immune cells underpins formation of hair follicles, has implications for scarless wound healing, and is critical for skin angiogenesis. We benchmarked a skin organoid model, derived from human embryonic stem (ES) and induced pluripotent stem (iPS) cells, against prenatal and adult skin, demonstrating close recapitulation of the epidermal and dermal skin components during hair follicle development. Notably, the skin organoid lacked immune cells and had markedly diminished endothelial cell heterogeneity and quantity. From our in vivo skin cell atlas data, we found that macrophages and macrophage-derived growth factors play a key role in driving endothelial development prenatally. Indeed, vascular network formation was enhanced following transfer of autologous iPS-derived macrophages into both endothelial cell angiogenesis assays and skin organoid cultures. In summary, innate immune cells moonlight as key players in skin morphogenesis beyond their conventional immune roles, a function they achieve via extensive crosstalk with non-immune cells. Finally, we leveraged our human prenatal skin cell atlas to further our understanding of the pathogenesis of genetic hair and skin disorders.

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Novel Blood Vascular Endothelial Subtype-Specific Markers in Human Skin Unearthed by Single-Cell Transcriptomic Profiling

Cited by 14 publications

References 73 publications

CD31 defines a subpopulation of human adipose-derived regenerative cells with potent angiogenic effects

CD31 defines a subpopulation of human adipose-derived regenerative cells with potent angiogenic effects

miR-709 exerts an angiogenic effect through a FGF2 upregulation induced by a GSK3B downregulation

A human prenatal skin cell atlas reveals immune cell regulation of skin morphogenesis

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