Organ-Specific Endothelial Cell Differentiation and Impact of Microenvironmental Cues on Endothelial Heterogeneity
Abstract
:1. Introduction
2. Development of Organ Specificity among Endothelial Cells
2.1. Vasculogenesis—Intrinsic Versus Extrinsic Factors
2.2. Large Conduit Vessel Differentiation
2.3. Organ-Specific Vascular Development
3. Technological Progress in Assessing Endothelial Cell Heterogeneity
4. Organ-Specific Endothelial Cell Culture and Phenotypic Drift
5. Role of the Tissue Microenvironment in Adult Endothelial Cell Heterogeneity
5.1. Mechanical Cues Determining Endothelial Cell Heterogeneity
Organ-Specific Responses to Tissue Stiffness, Shear Stress, and Cellular Stretch
5.2. Biochemical Cues Determining Endothelial Cell Heterogeneity
Organ-Specific Responses to Specific Biochemical Cues
6. Impact of Endothelial Cell Heterogeneity on Drug Development
Organ/ Tissue | Cell Type | Pass. Nr. | Co-Culture | Tissue Mimicking | Characterization Technique | Time in Culture | Refs | |||
---|---|---|---|---|---|---|---|---|---|---|
Mechanical | Biochemical | Genetics | Morphology | Function | ||||||
Brain | human brain microvascular (mv) ECs (HBMECs) (C) | P2–P3 | human astrocytes | 6.2 dynes/cm2; PP hollow fibers | FN | RNA microarray | - | TEER; glucose consumption and lactate production | 30 d | [118] |
P4–P7 | - | 10–20, 40 dynes/cm2; silicone | FN + Astrocyte conditioned medium | - | IF: CD31, ZO-1 and CLDN-5; WB: Transport markers P-gp and GLUT1 | Src/ERK pathway activation | 4 d | [161] | ||
bovine primary BMECs (F) | P1–P7 | Glial cells (astrocytes >95%) (F) | - | Col solution | - | IF: CLDN, OCLN, ZO, β-cat, p120cat, actin cytoskeleton | Permeability assays | 14 d | [129] | |
mouse primary BMECs (F) | P1 | - | - | Matrigel | RNA-seq, transcriptome | IF: CLDN-5, OCLN, ZO-1, ZO-2, JAM-A, VE-cad & β-cat | TEER | 7 d | [130] | |
mouse primary BECs (F) | P1 | - | - | Col I | RNA-seq and ATAC-seq | IF: CD31 | - | 10 d | [131] | |
iPSCs-derived HBMECs & human umbilical vein ECs (HUVECs) (D) | P1–P7 | - | ~4 dynes/cm2; cylindrical 150 μm Ø channel Col hydrogel | Col I | GLUT1 and P-gp expression | IF: ZO-1, CLDN-5 and OCLN | Permeability assays | 6 d | [133] | |
iPSCs-derived HBMECs (D) | P2 | - | - | Genipin-crosslinked Col I gels, with FN and Col IV | - | IF: ZO-1 and CLDN-5 | TEER, microvessel formation | 7 d | [135] | |
hESCs-derived ECs (D) | - | hESCs-derived cortical organoids | Perfusion tests | cortical organoids | TJ & nutrient transporter expression; single-cell map vhCOs | - | TEER | 120 d | [134] | |
Immortalized mouse BMECs (bEnd3) (C) | - | patient-derived glioblastoma cells | Alginate fibers | thiolated sodium hyaluronate | qPCR | IF | VEGF release | 14 d | [119] | |
Immortalized HBMECs; HUVECs (C) | - | - | 8, 12, 16 dynes/cm2 | - | - | IF: F-actin and ZO-1; WB: β-catenin and ZO-1; cell alignment | - | 36 h | [120] | |
Lung | human pulmonary artery ECs (HPAECs) (C) | P6–P8 | - | flexible-bottomed BioFlex plates; 5 and 18% elongation cyclic stretch | Col I | gene profiling | IF: F-actin; stress fiber & actin alignment; WB: pathway factors | cytoskeletal rearrang. & TEER | 2 d | [121] |
P7–P10 | - | 1, 3, 8 dynes/cm2; glass | Gelatin | - | IF: MitoTracker and caveolin-1 | Real-time imaging: mit. ATP levels; Ca2+ influx | few min | [122] | ||
human pulmonary mv ECs (HPMECs) (C) | P4–P7 | - | silicon chamber; 10, 20, 30% stretch strains | FN | qPCR: TRPV-2, TRPV-4 | IF: Tie-2, CD31, F-actin | Stretch-activated Ca2+ influx | few min | [123] | |
mouse primary PMECs & cardiac mv ECs (both E4ORF1) (C) | - | - | 4 dynes/cm2; PS slides | FN | - | FC: CD31, CD144; cell alignment & area; AFM: cell stiff. | - | 12 h | [124] | |
- | - | 2 dynes/cm2; PDMS (500 kPa) and PS (2–3 GPa) slides | Cardiac & lung ECM vs. FN | - | cell alignment and area; FC: integrins αv and β3 | - | 12 h | [125] | ||
Heart | bovine primary aortic ECs (F) | - | - | 12 dynes/cm2; glass; 100 pN pulsatile & 10 pN continuous forces | FN or Col I | - | WB: RhoA, ph-CREB, ph-PKA, PKA, ph-serine; IF: actin, vinculin, β-cat, HUTS-4, VE-cad | Bead displacement by pulsatile force; cAMP; integrin activation | 30 min | [169] |
HPMEC-ST1.6R (F) | - | Adipose tissue-derived stromal cells | Left ventricle-, mitral valve-, aorta-derived hydrogels (3, 3, 7 kPa) | Left ventricle, mitral valve & aorta ECM | - | IF: SM22α, actin, CD31 | Vascular network formation | 7 d | [132] | |
Liver | HUVECs (F) | - | fetal liver cells | perfusion at 0.5 mL/min; liver decellularized scaffolds | Liver decellular. ECMs; matrigel | - | IF: vWF, eNOS, Ki67, TUNEL | Vascular network formation; prolif.; platelet deposition | 7 d | [138] |
Unspecific | HUVECs (C) | - | - | 20 dynes/cm2; ibidi slides | - | qPCR: Wnt ligands | cell polarity & orientation; IF: Cleaved Caspase-3, Col IV, Erg1/2/3, GM130, Golph4, ICAM2, Lef1, NG2; FC: CD31, CD45 | - | 4 h | [139] |
HUVECs (C) | P6–P10 | THP1 cells | FITC-conjugated dextran flow | 15(S)-hydroxyeicosatetraenoic acid | - | IF: ZO-1, OCLN | Barrier permeability & disruption; THP1 transmigration | 8 h | [199] | |
bovine aorta ECs & HUVECs (C) | P6–P10 | - | 6, 12, 18 & 22 dynes/cm2; 100 Pa, 2.5, 3, 10 & 30 kPa PAA gels | FN | - | cell alignment & area; IF: actin, NF-κB | TNF-α induced NF-κB transloc. to nucleus | 24 h | [128] | |
human pulmonary artery ECs (HPAECs) (C) | P5–P9 | - | 1.1 & 40 kPa hydrogels, or glass (~50 GPa) | FN or Col IV | - | IF: VE-cad, paxillin, actin | Magnetic twisting cytometry for VE-cad receptor perturbation & displacement; Monolayer stress microscopy | 5 d | [200] | |
immortalized human mv ECs (HMEC-1) & HUVECs (C) | P4–P8 | - | 3, 35 & 70 kPa PAA gels | Col I | Transcriptom. and qPCR | IF: pMLC & actin & WB | Traction force microscopy | 2 h | [156] | |
human umbilical artery ECs (HUAECs) & HUVECs (C) | - | - | - | Col I; hypoxia | qPCR: β-actin, HPRT1 | FC: VE-cad, CD31, KDR, CD146, PDGFRβ; IF & WB: Col I, Col IV, FN, laminin, actin | Hypoxia & conditioned ECM deposition | 7 d | [140] | |
Diverse | fetal human primary kidney, lung, liver & heart ECs (F) | P2–P5 | rat primary hepatocytes | Gravity-driven flow; cells in Col microfluidic channels | Col I | RNAseq of freshly isolated vs. cultured ECs | IF: CD31, CD144, vWF, PV1 & Caveolin 1 | TEER, spheroid sprouting, metabolic assays | 5 d | [106] |
human primary mv dermal, lung, renal glomerular, brain & liver ECs; large vessel coronary artery ECs & HUVECs (C) | P2–P8 | - | - | Dilutions of TTP/sporadic HUS patients’ plasma | qPCR: Fas transcripts | FC: annexin II | Apoptosis: Cdc2 kinase assay, procoagulant activities | 16-18 h | [126] | |
human primary mv cardiac, dermal, lung & uterine ECs; aortic, cardiac artery, iliac ECs, HPAECs & HUVECs (C) | P2–P6 | - | - | Hypoxia | Gene expression microarray; qPCR: HIF1A, HIF-2a, 18S, TBP | WB: HIF-1a, HIF-2a; β-actin | Hypoxia effects in transcriptome | 2 d | [127] | |
human adipose-derived endothelial cells & HUVECs (F); human mv cardiac, aortic, pulmonary and dermal ECs (C); ETV2-transduced. | P5–P10 | Colorect. cancer, colon & small intestine organoids;pancreat. islets | Gravity-driven perfusion tests in microfluidic devices | Matrigel or mixture of laminin, entactin & col IV | single-cell transcriptom. & epigenetics | IF: VE-cad, CD31, PDGFRβ; FC: CD31, CD45; WB: RAP1, ETV2, ETS1, p-AKT; vessel area | Vascular tube formation; glucose-responsive insulin-secreting (islets); intestine & organoid vascularization | 12 w | [136] |
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Conflicts of Interest
References
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Gifre-Renom, L.; Daems, M.; Luttun, A.; Jones, E.A.V. Organ-Specific Endothelial Cell Differentiation and Impact of Microenvironmental Cues on Endothelial Heterogeneity. Int. J. Mol. Sci. 2022, 23, 1477. https://doi.org/10.3390/ijms23031477
Gifre-Renom L, Daems M, Luttun A, Jones EAV. Organ-Specific Endothelial Cell Differentiation and Impact of Microenvironmental Cues on Endothelial Heterogeneity. International Journal of Molecular Sciences. 2022; 23(3):1477. https://doi.org/10.3390/ijms23031477
Chicago/Turabian StyleGifre-Renom, Laia, Margo Daems, Aernout Luttun, and Elizabeth A. V. Jones. 2022. "Organ-Specific Endothelial Cell Differentiation and Impact of Microenvironmental Cues on Endothelial Heterogeneity" International Journal of Molecular Sciences 23, no. 3: 1477. https://doi.org/10.3390/ijms23031477