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. 2023 Nov 16;189(6):780-783.
doi: 10.1093/bjd/ljad330.

Endothelial cells differentiated from patient dermal fibroblast-derived induced pluripotent stem cells resemble vascular malformations of port-wine birthmark

Vi Nguyen  1 , Chao Gao  1 , Marcelo L Hochman, Jacob Kravitz  1 , Elliott H Chen, Harold I Friedman, Camilla F Wenceslau  1   2 , Dongbao Chen, Yunguan Wang  3 , J Stuart Nelson, Anil G Jegga  3   4 , Wenbin Tan  1   2
Affiliations

Endothelial cells differentiated from patient dermal fibroblast-derived induced pluripotent stem cells resemble vascular malformations of port-wine birthmark

Vi Nguyen et al. Br J Dermatol. .

Abstract

Lesional induced pluripotent stem cell-derived endothelial cells can resemble pathological vascular phenotypes of port-wine birthmark (PWB). Our data demonstrate that multiple pathways, including Hippo and Wnt, NFκB, TNF, MAPK and cholesterol metabolism, are dysregulated. These data suggest new therapeutics can be developed to target such dysregulated pathways in the treatment of PWB.

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Conflict of interest statement

Conflicts of interest A.G.J. is a member of the Scientific Advisory Board of Gen1E Lifesciences, USA. W.T. is a shareholder of TritaliMed, USA. The other authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Generation and functional characterization of port-wine birthmark (PWB)-derived induced pluripotent stem cells (iPSCs) and their differentiated endothelial cells (ECs). (a) Typical morphology of a control iPSC colony, ctl_iPSC_52521_8. (b) Alkaline phosphatase (AP) staining of the PWB iPSC 4221_3 colony. (c) PWB_iPSC_4221_6 colony-expressing stem cell biomarkers Nanog and Tra1-60 (image overlay). (d) Stem cell biomarkers Sox2 and Oct4 (image overlay) were used to stain control iPSCs. (e) Fully differentiated monolayer ECs from PWB iPSCs were observed on day 8 during differential induction. (f) PWB iPSC-derived ECs expressed membrane biomarkers CD31 (red) and CD144 (green; image overlay). Nuclei were stained by 4′,6-diamidino-2-phenylindole (DAPI). (a–f) Yellow scale bar = 100 µm. (g) Control EC_52521_9 and (h) PWB EC_4221_3 formed capillary-like structures (CLS) on GeltrexTM. (i) PWB EC_4221_3 showed impaired CLS in vitro with larger perimeters (P = 5.09 × 10–32) than the control EC_52521_9. Whiskers indicate mean (SD), diamond boxes indicate the interquartile range, and dotted curves indicate the data distribution. Mann–Whitney U test was used. (j, k) Formation of perfused human vasculature 10 days after intradermal xenograft of the (j) control and (k) PWB ECs with corresponding mesoderm/mesenchymal stem cells (MSCs) into severe combined immunodeficiency mice. Arrows indicate perfused blood vessels in xenografts comprising human ECs, confirmed by immunohistochemistry by an antihuman Ulex europaeus agglutinin 1 (UEA1) antibody. (l) Perimeter distribution of xenografted vasculature formed by PWB ECs vs. control ECs. Pink dashed rectangle indicates the total percentage (41.2%) of perfused vessels formed by PWB iPSC-derived ECs vs. 16.5% of perfused vessels formed by control iPSC-derived ECs with perimeters > 100 µm. (m) Functional interaction network of Hippo- and Wnt-related differentially expressed genes (DEGs) in PWB vasculature showing significant enrichment (false discovery rate < 0.05) for tube morphogenesis, endothelium and vasculature development, and EC differentiation. (n, o) KEGG enrichment analysis showing the top significantly (n) upregulated and (o) downregulated pathways related to vascular differentiation and development in PWB iPSCs and ECs. cAMP, cyclic adenosine monophosphate; ECM, extracellular matrix; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; NFκB, nuclear factor κB; PI3K, phosphoinositide 3-kinase; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor.
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