The versican-hyaluronan complex provides an essential extracellular matrix niche for Flk1+ hematoendothelial progenitors

Nandadasa, Sumeda; O’Donnell, Anna; Midura, Ronald J.

doi:10.1101/753418

Cited by 3 publications

(4 citation statements)

References 71 publications

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“…This notion was corroborated by a recent study showing that HA glycosaminoglycans are closely associated with early Flk1 + hematoendothelial cell progenitors during gastrulation and act as a cytokine trap to enhance VEGF-mediated angiogenesis and primitive hematopoiesis. 71 Our previous data have shown that kitlgb-kitb signaling is essential for maintaining runx1 expression and HSPC specification in the HE. 27 However, we and others 64 have demonstrated that kitlgb is highly expressed in the posterior blood island but not in the aortic HE region.…”

Section: Discussionmentioning

confidence: 95%

Hapln1b, a central organizer of the ECM, modulates kit signaling to control developmental hematopoiesis in zebrafish

et al. 2021

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During early vertebrate development, hematopoietic stem and progenitor cells (HSPCs) are produced from hemogenic endothelium located in the dorsal aorta, before they migrate to a transient niche where they expand, the fetal liver and the caudal hematopoietic tissue (CHT), in mammals and zebrafish, respectively. In zebrafish, previous studies have shown that the extracellular matrix (ECM) around the aorta needs to be degraded to allow HSPCs to leave the aortic floor and reach blood circulation. However, the role of the ECM components in HSPC specification has never been addressed. We show here that hapln1b, a key component of the ECM is specifically expressed in hematopoietic sites in the zebrafish embryo. Gain- and loss-of-function experiments all resulted in the absence of HSPCs in the early embryo, showing that hapln1b is required, at the correct level, to specify HSPCs in the hemogenic endothelium. Furthermore, we show that the expression of hapln1b is necessary to maintain the integrity of the ECM through its link domain. By combining functional analyses and computer modelling, we show that kitlgb interacts with the ECM to specify HSPCs. We demonstrate that the ECM is an integral component of the microenvironment and mediates cytokine signalling that is required for HSPC specification.

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Section: Discussionmentioning

confidence: 95%

Hapln1b, a central organizer of the ECM, modulates kit signaling to control developmental hematopoiesis in zebrafish

et al. 2021

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“…Prior work had showed accumulation of ADAMTS9 substrates versican and fibronectin in the ECM of ADAMTS9 mutant D12 cells when compared to the parental RPE-1 cells (12, 34). Both substrates are relevant to cell adhesion, with versican being anti-adhesive (35-37) and fibronectin being pro-adhesive (38, 39).…”

Section: Resultsmentioning

confidence: 99%

“…Versican had previously emerged as a key anti-adhesive ADAMTS9 substrate in human myometrial SMCs, since they formed few focal adhesions after ADAMTS9 knockdown and versican accumulated in Adamts9-deficient mouse myometrium; moreover, focal adhesions were restored dramatically by versican knockdown concomitant with ADAMTS9 knockdown in human myometrial SMCs (14). Versican, which also accumulates in the ECM of D12 cells when cultured for 72 h or longer (12,34), is likely also relevant to altered adhesion of D12 cells, although the possibility was not specifically experimentally addressed here. MT1-MMP knockdown had a restorative effect on fibrillar adhesion formation by D12 cells, suggesting that the complex tissue and cell phenotypes resulting from ADAMTS9 and ADAMTS20 deficiency reflect the impaired cleavage of more than one substrate, i.e., MT1-MMP, versican and potentially others.…”

Section: Discussionmentioning

confidence: 99%

Degradomic identification of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14) as an ADAMTS9 and ADAMTS20 substrate

Nandadasa¹,

Martin²,

Deshpande³

et al. 2022

Preprint

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The secreted metalloproteases ADAMTS9 and ADAMTS20 are implicated in extracellular matrix (ECM) proteolysis and primary cilium biogenesis. Here, we show that clonal gene-edited RPE-1 cells in which ADAMTS9 was inactivated, and which constitutively lack ADAMTS20 expression, have morphologic characteristics distinct from parental RPE-1 cells. To investigate underlying proteolytic mechanisms, a quantitative N-terminomics method, terminal amine isotopic labeling of substrates (TAILS) was used to compare parental and gene-edited cells and their medium to identify ADAMTS9 substrates. Among differentially abundant N-terminally labeled internal peptides arising from secreted and transmembrane proteins, a peptide with lower abundance in the medium of gene-edited cells suggested cleavage at the Tyr314-Gly315 bond in the ectodomain of the transmembrane metalloprotease MT1-MMP, whose mRNA was also reduced in gene-edited cells. This cleavage, occurring in the MT1-MMP hinge i.e., between the catalytic and hemopexin domains, was orthogonally validated both by lack of an MT1-MMP catalytic domain fragment in the medium of gene-edited cells and restoration of its release from the cell surface by re-expression of ADAMTS9 and ADAMTS20, and was dependent on hinge O-glycosylation. Since MT1-MMP is a type I transmembrane protein, identification of an N-terminally labeled peptide in the medium suggested additional downstream cleavage sites in its ectodomain. Indeed, a C-terminally semi-tryptic MT1-MMP peptide with greater abundance in wild-type RPE-1 medium identified by a targeted search indicated a cleavage site in the hemopexin domain. Consistent with retention of MT1-MMP catalytic domain on the surface of gene-edited cells, pro-MMP2 activation, which requires cell-surface MT1-MMP, was increased. MT1-MMP knockdown in gene-edited ADAMTS9/20-deficient cells restored focal adhesions but not ciliogenesis. The findings expand the web of interacting proteases at the cell-surface, suggest a role for ADAMTS9 and ADAMTS20 in regulating cell-surface activity of MT1-MMP and indicate that MT1-MMP shedding does not underlie their observed requirement in ciliogenesis.

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“…Acting as a transmembrane protein, TMEM2 is associated with tumor invasion and angiogenesis [28,29] and manipulates cell adhesion and metastasis by degrading nonprotein components of the extracellular matrix [30]. Gastric cancer prognosis is positively related to GUCY1A2 [31], which plays a vital role in rheumatoid arthritis development [32], and afects SARS-CoV 2 infections and drug repurposing [33].…”

Section: Discussionmentioning

confidence: 99%

Identification of Diagnostic Markers in Infantile Hemangiomas

Huang

Chen

Gao

et al. 2022

Journal of Oncology

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Background. Infantile Hemangiomas (IHs) are common benign vascular tumors of infancy that may have serious consequences. The research on diagnostic markers for IHs is scarce. Methods. The “limma” R package was applied to identify differentially expressed genes (DEGs) in developing IHs. Plugin ClueGO in Cytoscape software performed functional enrichment of DEGs. The Search Tool for Retrieving Interacting Genes (STRING) database was utilized to construct the PPI network. The least absolute shrinkage and selection operator (LASSO) regression model and support vector machine recursive feature elimination (SVM-RFE) analysis were used to identify diagnostic genes for IHs. The receiver operating characteristic (ROC) curve evaluated diagnostic genes’ discriminatory ability. Single-gene based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was conducted by Gene Set Enrichment Analysis (GSEA). The chemicals related to the diagnostic genes were excavated by the Comparative Toxicogenomics Database (CTD). Finally, the online website Network Analyst was used to predict the transcription factors targeting the diagnostic genes. Results. A total of 205 DEGs were singled out from IHs samples of 6-, 12-, and 24-month-old infants. These genes principally participated in vasculogenesis and development-related, endothelial cell-related biological processes. Then we mined 127 interacting proteins and created a network with 127 nodes and 251 edges. Furthermore, LASSO and SVM-RRF algorithms identified five diagnostic genes, namely, TMEM2, GUCY1A2, ISL1, WARS, and STEAP4. ROC curve analysis results indicated that the diagnostic genes had a powerful ability to distinguish IHs samples from normal samples. Next, the results of GSEA for a single gene illustrated that all five diagnostic genes inhibited the “valine, leucine, and isoleucine degradation” pathway in the development of IHs. WARS, TMEM2, and STEAP4 activated the “blood vessel development” and “vasculature development” in IHs. Subsequently, inhibitors targeting TMEM2, GUCY1A2, ISL1, and STEAP4 were mined. Finally, 14 transcription factors regulating GUCY1A2, 14 transcription factors regulating STEAP4, and 26 transcription factors regulating ISL1 were predicted. Conclusion. This study identified five diagnostic markers for IHs and further explored the mechanisms and targeting drugs, providing a basis for diagnosing and treating IHs.

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The versican-hyaluronan complex provides an essential extracellular matrix niche for Flk1+ hematoendothelial progenitors

Cited by 3 publications

References 71 publications

Hapln1b, a central organizer of the ECM, modulates kit signaling to control developmental hematopoiesis in zebrafish

Hapln1b, a central organizer of the ECM, modulates kit signaling to control developmental hematopoiesis in zebrafish

Degradomic identification of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14) as an ADAMTS9 and ADAMTS20 substrate

Identification of Diagnostic Markers in Infantile Hemangiomas

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