Inductive signals in branching morphogenesis – lessons from mammary and salivary glands

Myllymäki, Satu-Marja; Mikkola, Marja L.

doi:10.1016/j.ceb.2019.07.001

Cited by 20 publications

(23 citation statements)

References 55 publications

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“…New branches are generated by clefting, wherein epithelial cells separate from one another as the result of localized deposition of ECM. The lumen forms later through a cavitation or hollowing-out process, leaving a bi-layered epithelium of luminal cells on the inside and basal cells on the outside (Myllymaki and Mikkola, 2019). Given these differences in tissue architecture, it is unsurprising that the exact mechanisms of branching appear to be different from those observed in the lung or kidney.…”

Section: Ecm-driven Clefting In the Salivary Glandmentioning

confidence: 99%

“…The initial embryonic rudiment does not form in the absence of FGF10 or FGFR2, and FGFR2-null cells are outcompeted in the TEB by their wild-type counterparts during branching morphogenesis (Gjorevski and Nelson, 2011). Receptor tyrosine kinase activity is essential for TEB growth and ductal elongation (Myllymaki and Mikkola, 2019). EGF signaling is also induced by estrogen binding to estrogen receptor α (ERα; ESR1) during puberty; epithelial cells of the mammary gland express an EGF ligand called amphiregulin (Areg) that signals via epidermal growth factor receptor (EGFR) to stromal cells (Gjorevski and Nelson, 2011).…”

Section: Growth-driven Propulsion In the Mammary Glandmentioning

confidence: 99%

“…Branching morphogenesis of the mammalian salivary gland occurs again by different mechanisms, in which the extracellular matrix (ECM) drives clefting of a multilayered epithelium. Salivary epithelial bud elongation and clefting occur in the presence of important signals from the surrounding mesenchyme, but in the absence of smooth muscle (Myllymaki and Mikkola, 2019;Wang et al, 2017). Finally, the mammary gland uses yet another set of strategies to generate a branched architecture.…”

Section: Introductionmentioning

confidence: 99%

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Branching morphogenesis

Goodwin

Nelson

2020

Development

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Over the past 5 years, several studies have begun to uncover the links between the classical signal transduction pathways and the physical mechanisms that are used to sculpt branched tissues. These advances have been made, in part, thanks to innovations in live imaging and reporter animals. With modern research tools, our conceptual models of branching morphogenesis are rapidly evolving, and the differences in branching mechanisms between each organ are becoming increasingly apparent. Here, we highlight four branched epithelia that develop at different spatial scales, within different surrounding tissues and via divergent physical mechanisms. Each of these organs has evolved to employ unique branching strategies to achieve a specialized final architecture.

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Section: Ecm-driven Clefting In the Salivary Glandmentioning

confidence: 99%

Section: Growth-driven Propulsion In the Mammary Glandmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Branching morphogenesis

Goodwin

Nelson

2020

Development

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“…The molecular and cellular mechanisms driving mammary branching morphogenesis have been studied extensively, yet embryonic development is poorly understood ( Myllymäki and Mikkola, 2019 ). The signaling pathways regulating early development are described to some extent, though.…”

Section: Introductionmentioning

confidence: 99%

Cell influx and contractile actomyosin force drive mammary bud growth and invagination

Trela

Lan

Myllymäki

et al. 2021

Journal of Cell Biology

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The mammary gland develops from the surface ectoderm during embryogenesis and proceeds through morphological phases defined as placode, hillock, bud, and bulb stages followed by branching morphogenesis. During this early morphogenesis, the mammary bud undergoes an invagination process where the thickened bud initially protrudes above the surface epithelium and then transforms to a bulb and sinks into the underlying mesenchyme. The signaling pathways regulating the early morphogenetic steps have been identified to some extent, but the underlying cellular mechanisms remain ill defined. Here, we use 3D and 4D confocal microscopy to show that the early growth of the mammary rudiment is accomplished by migration-driven cell influx, with minor contributions of cell hypertrophy and proliferation. We delineate a hitherto undescribed invagination mechanism driven by thin, elongated keratinocytes—ring cells—that form a contractile rim around the mammary bud and likely exert force via the actomyosin network. Furthermore, we show that conditional deletion of nonmuscle myosin IIA (NMIIA) impairs invagination, resulting in abnormal mammary bud shape.

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“…A deeper investigation of the aforementioned growth factors can be used to generate organoids from teeth, salivary glands, and the mammary gland. Understanding the differentiation hierarchy of mammary, salivary, and dental stem cells ( Jussila and Thesleff, 2012 ; Myllymäki and Mikkola, 2019 ; Visvader and Stingl, 2014 ) will be important to generate PSC-derived mammary organoids. Although a mosaic mammary gland is generated by reprogramming dental epithelial stem cells mixed with mammary epithelial cells (MECs) ( Jimenez-Rojo et al, 2019 ) or by mixing mESCs with MECs ( Boulanger et al., 2013 ), generating organoids is not reported.…”

Section: Mimicking Development To Generate Multi-lineage Organoidsmentioning

confidence: 99%

Translating Embryogenesis to Generate Organoids: Novel Approaches to Personalized Medicine

Sahu

Sharan

2020

iScience

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Summary The astounding capacity of pluripotent stem cells (PSCs) to differentiate and self-organize has revolutionized the development of 3D cell culture models. The major advantage is its ability to mimic in vivo microenvironments and cellular interactions when compared with the classical 2D cell culture models. Recent innovations in generating embryo-like structures (including blastoids and gastruloids) from PSCs have advanced the experimental accessibility to understand embryogenesis with immense potential to model human development. Taking cues on how embryonic development leads to organogenesis, PSCs can also be directly differentiated to form mini-organs or organoids of a particular lineage. Organoids have opened new avenues to augment our understanding of stem cell and regenerative biology, tissue homeostasis, and disease mechanisms. In this review, we provide insights from developmental biology with a comprehensive resource of signaling pathways that in a coordinated manner form embryo-like structures and organoids. Moreover, the advent of assembloids and multilineage organoids from PSCs opens a new dimension to study paracrine function and multi-tissue interactions in vitro . Although this led to an avalanche of enthusiasm to utilize organoids for organ transplantation studies, we examine the current limitations and provide perspectives to improve reproducibility, scalability, functional complexity, and cell-type characterization. Taken together, these 3D in vitro organ-specific and patient-specific models hold great promise for drug discovery, clinical management, and personalized medicine.

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Inductive signals in branching morphogenesis – lessons from mammary and salivary glands

Cited by 20 publications

References 55 publications

Branching morphogenesis

Branching morphogenesis

Cell influx and contractile actomyosin force drive mammary bud growth and invagination

Translating Embryogenesis to Generate Organoids: Novel Approaches to Personalized Medicine

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