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Molecular mechanisms of tubulogenesis revealed in the sea star hydro-vascular organ.

ABSTRACT: A fundamental goal in the organogenesis field is to understand how cells organize into tubular shapes. Toward this aim, we have established the hydro-vascular organ in the sea star Patiria miniata as a model for tubulogenesis. In this animal, bilateral tubes grow out from the tip of the developing gut, and precisely extend to specific sites in the larva. This growth involves cell migration coupled with mitosis in distinct zones. Cell proliferation requires FGF signaling, whereas the three-dimensional orientation of the organ depends on Wnt signaling. Specification and maintenance of tube cell fate requires Delta/Notch signaling. Moreover, we identify target genes of the FGF pathway that contribute to tube morphology, revealing molecular mechanisms for tube outgrowth. Finally, we report that FGF activates the Six1/2 transcription factor, which serves as an evolutionarily ancient regulator of branching morphogenesis. This study uncovers distinct mechanisms of tubulogenesis in vivo and we propose that cellular dynamics in the sea star hydro-vascular organ represents a key comparison for understanding the evolution of vertebrate organs.

SUBMITTER: Perillo M

PROVIDER: S-EPMC10170166 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Molecular mechanisms of tubulogenesis revealed in the sea star hydro-vascular organ.

Perillo Margherita M Swartz S Zachary SZ Pieplow Cosmo C Wessel Gary M GM

Nature communications 20230509 1

A fundamental goal in the organogenesis field is to understand how cells organize into tubular shapes. Toward this aim, we have established the hydro-vascular organ in the sea star Patiria miniata as a model for tubulogenesis. In this animal, bilateral tubes grow out from the tip of the developing gut, and precisely extend to specific sites in the larva. This growth involves cell migration coupled with mitosis in distinct zones. Cell proliferation requires FGF signaling, whereas the three-dimens ...[more]

PMID: 37160908

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Project description:Stem cell-based therapies are a promising new avenue for treating ischemic disease and chronic wounds. Mesenchymal stem cells (MSCs) have a proven ability to augment the neovascularization processes necessary for wound healing and are widely popular as an autologous source of progenitor cells. Our lab has previously reported on PEGylated fibrin as a unique hydrogel that promotes spontaneous tubulogenesis of encapsulated MSCs without exogenous factors. However, the mechanisms underlying this process have remained unknown. To better understand the therapeutic value of PEGylated fibrin delivery of MSCs, we sought to clarify the relationship between biomaterial properties and cell behavior. Here we find that fibrin PEGylation does not dramatically alter the macroscopic mechanical properties of the fibrin-based matrix (less than 10% difference). It does, however, dramatically reduce the rate of diffusion through the gel matrix. PEGylated fibrin enhances the tubulogenic growth of encapsulated MSCs demonstrating fluid-filled lumens by interconnected MSCs. Image analysis gave a value of 4320 ± 1770 μm total network length versus 618 ± 443 μm for unmodified fibrin. PEGylation promotes the endothelial phenotype of encapsulated MSCs--compared to unmodified fibrin--as evidenced by higher levels of endothelial markers (von Willebrand factor, 2.2-fold; vascular endothelial cadherin, 1.8-fold) and vascular endothelial growth factor (VEGF, up to 1.8-fold). Prospective analysis of underlying molecular pathways demonstrated that this endothelial-like MSC behavior is sensitively modulated by hypoxic stress, but not VEGF supplementation as evidenced by a significant increase in VEGF and MMP-2 secretion per cell under hypoxia. Further gain-of-function studies under hypoxic stress demonstrated that hypoxia culture of MSCs in unmodified fibrin could increase both vWF and VE-cadherin levels to values that were not significantly different than cells cultured in PEGylated fibrin. This result corroborated our hypothesis that the diffusion-limited environment of PEGylated fibrin is augmenting endothelial differentiation cues provided by unmodified fibrin. However, MSC networks lack platelet endothelial cell adhesion molecule-1 (PECAM-1) expression, which indicates incomplete differentiation towards an endothelial cell type. Collectively, the data here supports a revised understanding of MSC-derived neovascularization that contextualizes their behavior and utility as a hybrid endothelial-stromal cell type, with mixed characteristics of both populations.

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Molecular mechanisms of tubulogenesis revealed in the sea star hydro-vascular organ.

Publications

Molecular mechanisms of tubulogenesis revealed in the sea star hydro-vascular organ.

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