Region‐specific epithelial cell dynamics during branching morphogenesis

Hsu, Jeff Chi-feng; Koo, Hyun; Harunaga, Jill S.; Matsumoto, Kazue; Doyle, Andrew D.; Yamada, Kenneth M.

doi:10.1002/dvdy.24028

Cited by 14 publications

(27 citation statements)

References 47 publications

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“…A gradient of speeds was observed, with the fastest cells located near the front (Spearman r=0.77 and P<0.0001). Similar regional differences in cell speed have been described in the mouse salivary gland, suggesting a conserved mechanism for epithelial tube elongation (Hsu et al, 2013). By contrast, despite variations within individual branches, persistence displayed no consistent correlation with distance from the front (Spearman r=−0.11 and a non-significant P-value) (Fig.…”

Section: Elongation Correlates With An Increase In Cell Motilitysupporting

confidence: 71%

“…Consistent with this conceptual model, we identified a gradient of cell speeds running from slow in the body of the organoid to fast in the high-pERK tips of elongating ducts. High levels of cell motility in the elongation front have also been observed in the mouse salivary gland (Hsu et al, 2013). We next demonstrated that both cell migration and branch elongation require Rac1 and MAPK signaling.…”

Section: The Cell Behavioral Basis Of Tube Elongationmentioning

confidence: 53%

“…Since mammalian organs increase in size and structural complexity during development, researchers have sought to understand the relative contributions of proliferation, cell shape change and migration to lung, salivary gland and kidney tubulogenesis (Andrew and Ewald, 2010;Alescio and Di Michele, 1968;Goldin and Wessells, 1979;Lubarsky and Krasnow, 2003). Recent advances in organotypic culture and imaging have shed light on how these processes drive mammalian tube growth and development (Shamir and Ewald, 2014;Kim et al, 2013;Schnatwinkel and Niswander, 2013;Packard et al, 2013;Larsen et al, 2006;Hsu et al, 2013;Tang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Mammary epithelial tubes elongate through MAPK-dependent coordination of cell migration

2016

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Mammary branching morphogenesis is regulated by receptor tyrosine kinases (RTKs). We sought to determine how these RTK signals alter proliferation and migration to accomplish tube elongation in mouse. Both behaviors occur but it has been difficult to determine their relative contribution to elongation in vivo, as mammary adipocytes scatter light and limit the depth of optical imaging. Accordingly, we utilized 3D culture to study elongation in an experimentally accessible setting. We first used antibodies to localize RTK signals and discovered that phosphorylated ERK1/2 ( pERK) was spatially enriched in cells near the front of elongating ducts, whereas phosphorylated AKT was ubiquitous. We next observed a gradient of cell migration speeds from rear to front of elongating ducts, with the front characterized by both high pERK and the fastest cells. Furthermore, cells within elongating ducts oriented both their protrusions and their migration in the direction of tube elongation. By contrast, cells within the organoid body were isotropically protrusive. We next tested the requirement for proliferation and migration. Early inhibition of proliferation blocked the creation of migratory cells, whereas late inhibition of proliferation did not block continued duct elongation. By contrast, pharmacological inhibition of either MEK or Rac1 signaling acutely blocked both cell migration and duct elongation. Finally, conditional induction of MEK activity was sufficient to induce collective cell migration and ductal elongation. Our data suggest a model for ductal elongation in which RTK-dependent proliferation creates motile cells with high pERK, the collective migration of which acutely requires both MEK and Rac1 signaling.

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Section: Elongation Correlates With An Increase In Cell Motilitysupporting

confidence: 71%

Section: The Cell Behavioral Basis Of Tube Elongationmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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Mammary epithelial tubes elongate through MAPK-dependent coordination of cell migration

2016

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“…E-cadherin plays an important role in the development of the SMG, [51][52][53][54][55] in particular to provide survival signals to maturing duct cells. 55 Recent studies have shown that cells dispersed from salivary gland tissues in mice and humans can self-assemble to acinar-like structures in vitro and display characteristics of native gland structures.…”

Section: Figmentioning

confidence: 99%

“…PEG hydrogels are bioinert, 26 and they lack cell-matrix and cell-cell interactions that are commonly utilized to maintain survivability of sensitive cell types. 32,38,41,49,50 As cell-cell interactions, in particular, play a vital role in salivary gland cell functions in vitro and during gland development, 20,[51][52][53][54][55][56][57] we also explored the use of SMG cell aggregation into microspheres to increase longterm viability of hydrogel-encapsulated SMG cells. Finally, we examined the cellular composition and proliferative potential of the encapsulated SMG microspheres.…”

mentioning

confidence: 99%

Development of Poly(Ethylene Glycol) Hydrogels for Salivary Gland Tissue Engineering Applications

Shubin

Felong

Graunke

et al. 2015

Tissue Engineering Part A

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More than 40,000 patients are diagnosed with head and neck cancers annually in the United States with the vast majority receiving radiation therapy. Salivary glands are irreparably damaged by radiation therapy resulting in xerostomia, which severely affects patient quality of life. Cell-based therapies have shown some promise in mouse models of radiation-induced xerostomia, but they suffer from insufficient and inconsistent gland regeneration and accompanying secretory function. To aid in the development of regenerative therapies, poly(ethylene glycol) hydrogels were investigated for the encapsulation of primary submandibular gland (SMG) cells for tissue engineering applications. Different methods of hydrogel formation and cell preparation were examined to identify cytocompatible encapsulation conditions for SMG cells. Cell viability was much higher after thiol-ene polymerizations compared with conventional methacrylate polymerizations due to reduced membrane peroxidation and intracellular reactive oxygen species formation. In addition, the formation of multicellular microspheres before encapsulation maximized cell-cell contacts and increased viability of SMG cells over 14-day culture periods. Thiol-ene hydrogel-encapsulated microspheres also promoted SMG proliferation. Lineage tracing was employed to determine the cellular composition of hydrogel-encapsulated microspheres using markers for acinar (Mist1) and duct (Keratin5) cells. Our findings indicate that both acinar and duct cell phenotypes are present throughout the 14 day culture period. However, the acinar:duct cell ratios are reduced over time, likely due to duct cell proliferation. Altogether, permissive encapsulation methods for primary SMG cells have been identified that promote cell viability, proliferation, and maintenance of differentiated salivary gland cell phenotypes, which allows for translation of this approach for salivary gland tissue engineering applications.

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Multiscale dynamics of branching morphogenesis

Hannezo

Simons

2019

Current Opinion in Cell Biology

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Branching morphogenesis is a prototypical example of complex three-dimensional organ sculpting, required in multiple developmental settings to maximize the area of exchange surfaces. It requires, in particular, the coordinated growth of different cell types together with complex patterning to lead to robust macroscopic outputs. In recent years, novel multiscale quantitative biology approaches, together with biophysical modelling, have begun to shed new light of this topic. Here, we wish review some of these recent developments, highlighting the generic design principles that can be abstracted across different branched organs, as well as the implications for the broader fields of stem cell, developmental and systems biology.

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Region‐specific epithelial cell dynamics during branching morphogenesis

Abstract: Background-Epithelial cells of developing embryonic organs, such as salivary glands, can display substantial motility during branching morphogenesis. Their dynamic movements and molecules involved in their migration are not fully characterized.

Cited by 14 publications

References 47 publications

Mammary epithelial tubes elongate through MAPK-dependent coordination of cell migration

Mammary epithelial tubes elongate through MAPK-dependent coordination of cell migration

Development of Poly(Ethylene Glycol) Hydrogels for Salivary Gland Tissue Engineering Applications

Multiscale dynamics of branching morphogenesis

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