Timing and Graded BMP Signalling Determines Fate of Neural Crest and Ectodermal Placode Derivatives from Pluripotent Stem Cells

Abstract

Pluripotent stem cells (PSCs) offer many potential research and clinical benefits due to their ability to differentiate into nearly every cell type in the body. They are often used as model systems to study early stages of ontogenesis to better understand key developmental pathways, as well as for drug screening. However, in order to fully realise the potential of PSCs and their translational applications, a deeper understanding of developmental pathways, especially in humans, is required. Several signalling molecules play important roles during development and are required for proper differentiation of PSCs. The concentration and timing of signal activation are important, with perturbations resulting in improper development and/or pathology. Bone morphogenetic proteins (BMPs) are one such key group of signalling molecules involved in the specification and differentiation of various cell types and tissues in the human body, including those related to tooth and otic development. In this review, we describe the role of BMP signalling and its regulation, the consequences of BMP dysregulation in disease and differentiation, and how PSCs can be used to investigate the effects of BMP modulation during development, mainly focusing on otic development. Finally, we emphasise the unique role of BMP4 in otic specification and how refined understanding of controlling its regulation could lead to the generation of more robust and reproducible human PSC-derived otic organoids for research and translational applications.

Keywords: bone morphogenetic proteins; human cell models; human pluripotent stem cells; organoids; otic lineage; pre-placodal ectoderm.

Figure 1

Effects of BMP concentration on fate of ectodermal cells to induce epidermal, placodal, neural crest, and neural derivatives. Exposure of pluripotent stem cells to different concentrations of BMP4 results in differentiation towards different cell fates via activation of various downstream genes. High concentration of BMP4 results in activation of genes such as K18, which causes cells to differentiate towards epidermal fate. Medium concentration of BMP4, which can be due to the presence of some inhibitors such as Noggin, causes activation of SIX1 for differentiation towards pre-placodal ectoderm and subsequent placodal lineages including lens, olfactory, and otic placodes. However, in the presence of WNT, neural crest fate is induced. Activation of genes such as Hes1 can have an inhibitory effect on this pathway. Low concentration of BMP4, which can be the result of high levels of Noggin due to Shh signalling or the presence of Chordin, results in activation of PAX6, NCAD, and other genes that result in neural fate. (Generated using Biorender.com, accessed 6 September 2024).

Figure 2

Overview of BMP signalling pathway and modulators during development of pre-placodal ectoderm. BMPs such as BMP4 bind to their receptors BMPR1A, BMPR1B, and BMPR2 on the cell surface, resulting in activation of SMADs which translocate to the nucleus to influence transcription of genes directing cell fate towards non-neural ectoderm/pre-placodal and subsequent placodal fates, and inhibiting differentiation towards neural fate. The presence of antagonists and modulators such as Noggin, Follistatin, Chordin, Gremlin, and TWSG1 alter the level of BMP activity on the cell and hence can also influence cell fate. (Generated using Biorender.com, accessed 6 September 2024).