Building bridges between fields: bringing together development and homeostasis

Abstract

Despite striking parallels between the fields of developmental biology and adult tissue homeostasis, these are disconnected in contemporary research. Although development describes tissue generation and homeostasis describes tissue maintenance, it is the balance between stem cell proliferation and differentiation that coordinates both processes. Upstream signalling regulates this balance to achieve the required outcome at the population level. Both development and homeostasis require tight regulation of stem cells at the single-cell level and establishment of patterns at the tissue-wide level. Here, we emphasize that the general principles of embryonic development and tissue homeostasis are similar, and argue that interactions between these disciplines will be beneficial for both research fields.

Keywords: Embryonic development; Patterning; Self-organization; Signalling; Stem cell control; Tissue homeostasis.

Fig. 1.

Strategies for cell fate determination. (A) A Drosophila neuroblast determines daughter cell fate by asymmetric localization of cell fate determinants. Initial polarization of Inscuteable (Insc), LGN, Nuclear mitotic apparatus protein (NuMA) and Dynein leads to eventual asymmetric localization and, hence, to asymmetric cell fate. GMC, ganglion mother cell; NB, neuroblast. (B) In the mammalian skin, polarity of stem cells is required for proper cell fate determination. However, no specific cell fate determinants have been found. Initial polarity is created by homologs of Insc, LGN, NuMA and Dynein. (C) Lgr5⁺ adult stem cells that maintain the small intestine during homeostasis reside in a niche located in the bottom of the crypt. Both Paneth cells and mesenchymal cells provide niche factors for stem cell maintenance. R-Spondin, Noggin, Egf and Wnt are secreted by mesenchymal cells, whereas Egf, Wnt3a and Notch are provided by the Paneth cells. (D) Neuromesodermal progenitors (NMPs), which give rise to the neural tube and the presomitic mesoderm, reside in a niche at the posterior tip of the vertebrate embryo. The source of niche factors Wnt, Fgf and Bmp remains to be elucidated.

Fig. 2.

Symmetry-breaking events. (A) Establishment of an apical domain in outer cells induces symmetry breaking from the outside to the inside of the early mouse embryo. Nuclear phosphorylated Yap (pYap) then induces activation of Cdx2 and the first lineage segregation into trophectoderm and inner cell mass (ICM). (B) Small intestine organoids are initially spherically symmetrical and break symmetry after withdrawal of Wnt supplements from the medium. Fluctuation in Yap1 signalling organize the formation of Paneth cells, the first differentiation of the maturing organoid.

Fig. 3.

Models for patterning. (A) Turing patterning is based on secretion of short-range activators and long-range inhibitors. By using of this mode of patterning, complex organization of cell types can occur, such as the labyrinth patterning of zebrafish skin. (B) Lateral inhibition is created by Notch signalling. Notch signalling is activated by the membrane-bound ligand Delta. Active Notch signalling results in downregulation of Delta and therefore inactive Notch signalling on neighbouring cells. Conversely, low Notch signalling results in high Delta and active Notch signalling in neighbouring cells. For example, lateral inhibition creates a salt-and-pepper pattern of cell fates in the Drosophila neuroectoderm. (C) The French flag problem is a gradient-based model of patterning. Information is encoded in the strength of the gradient. Cells positioned at different locations within a gradient receive different signals and therefore behave/differentiate differently. For example, a neuronal pattern arises based on the position of neuronal precursors within a gradient.

Fig. 4.

Gradients and signalling dynamics during somitogenesis and small intestine homeostasis. (A) Somitogenesis is coordinated by posterior gradients of Wnt and Fgf, and an anterior antagonistic gradient of retinoic acid (RA). Neuromesodermal progenitors (NMPs) from the posterior migrate along the posterior gradient, and concomitantly differentiate and form somites when they reach the determination front. Further patterning is achieved by signalling dynamics. Somites form in a rhythmic manner and periodicity is determined by oscillatory activation of Wnt, Fgf and Notch signalling. In the posterior presomitic mesoderm, Wnt and Notch signalling oscillate out of phase, while in the anterior, Notch and Wnt signalling are synchronized. (B) The small intestine is patterned by many gradients, including Wnt and Egf gradients originating from the crypt side and an antagonistic Bmp gradient originating from the villus. Lgr5⁺ adult stem cells progress into transit amplifying (TA) cells and finally differentiate into their terminal state. This differentiation trajectory occurs along the crypt side gradient. Lgr5⁺ stem cells are maintained in the crypt by lateral inhibition of Notch by Paneth cells. Although gradients and lateral inhibition are found to be necessary during small intestinal homeostasis, the importance of signalling dynamics remains elusive. Pulsatile Erk dynamics have been found during organoid formation (Muta et al., 2018); however, dynamics within the Notch and Wnt signalling pathways are yet to be explored.