Neuromesodermal Progenitors: Function and Significance

By Daniella Gimbosh

Stem cells are a revolutionary and controversial area of science that often, understandably, overshadow other aspects of developmental biology. Stem cells are able to divide over and over again, producing more copies of identical stem cells with the same properties, or giving rise to many different types of cells in the body. These cells are considered as precursor or progenitor cells and can either be pluripotent, meaning that they can give rise to every type of cell in the body, or multipotent, meaning that they can give rise to a limited number of different cell types within a lineage.1 However, a myriad of other cells exist that are crucial for the development of an embryo, and many remain largely undiscovered. 

During the development of an embryo, specific progenitor cells give rise to the different tissues and layers of the embryo, such as the tissue of the central nervous system (CNS). The cells that give rise to the vast majority of neural cells that make up the CNS in an embryo are called neural progenitor cells (NPCs). NPCs are not only found in the embryo, they have even been found in an adult brain, although with less differentiation potential than their embryonic counterparts.2 The location in the CNS, gene expression profile, developmental role and structural features of the NPCs are what characterize them into different subtypes. 

In the early stages of embryo development, the vertebral axis begins to develop and elongate. This occurs through an amalgamation of events including tissue formation and NPC growth in various body axis regions. The order in which these events occur, and the way they coordinate with each other in order to create the body axis, remains a large gap in the current embryological literature.3 In order for scientists to fully understand vertebral body axis formation, these events must first be investigated.

As aforementioned, various progenitors are essential for the development of the vertebrate body axis in an embryo. Specifically, it is the axial progenitors that are required. These are NPCs found in the caudal progenitor zone. As the vertebral body grows, at the posterior embryonic region a type of bipotent progenitor called neuromesodermal progenitor (NMP) is able to generate two different types of derivatives: neural (giving rise to the spinal cord) and paraxial mesoderm (the area of the mesoderm that gives rise to the axial skeleton).4 Pluripotent stem cells are able to give rise to NMPs, and this specific cellular state of NMPs is vital for the development of the muscles and spinal cord.5 Interestingly, the spatiotemporal location of NMPs is usually coordinated with the expression of specific transcription factors, such as Sox2.6 

Recent literature improves our understanding of these NMPs and allows us to address a range of biomedical science questions that could have major implications in the fields of both regenerative medicine and disease modelling. For example, recent studies suggest that neural progenitors derived from specific parts of the neuraxis have different roles and therefore result in important regional variations.5 Additionally, the fact that NMPs can be produced from pluripotent stem cells emphasizes their potential in regenerative medicine, developmental biology and spinal cord injury (SCI) treatment. 

Specifically, the possibility of engineering NMP cells from pluripotent stem cells in vitro has enormous implications for SCIs. Although the generation of neural cells using pluripotent stem cells for SCI treatment has previously been suggested7, the development of specifically NMPs in vitro to generate spinal cord cells is a very novel one. Research has suggested not only that transplantation of neural cells may be a possible treatment for SCIs, but also that if the axial identity of these cells, together with injury location, is considered, recovery may be improved8,9. While more experimentation is needed to draw significant conclusions, the possible benefit of NMP cell engineering for SCI cell therapy is undeniable.

Moreover, the generation of NMPs in vitro also has the potential to stimulate developments in human disease modeling and regenerative medicine. For example, an in vitro 3D model of an entire neuromuscular junction can be generated from just one neuromesodermal-competent region (a region where NMPs reside).5,10

Finally, novel research on NMPs improves our understanding of vertebral body axis formation during embryonic development, and gives remarkable insights for medical and translational applications in a clinical setting. Thus, working towards developing specific NMP cell subtypes in vitro could be the key to expanding human disease modeling possibilities, and developing personalised cell-based therapies in the fields of developmental and regenerative medicine. 

References:

1. Bindu A H, B S. Potency of Various Types of Stem Cells and their Transplantation. Journal of Stem Cell Research & Therapy. [Online] 2011;01(03). Available from: doi:10.4172/2157-7633.1000115 [Accessed: 6th November 2021]

2. Martínez-Cerdeño V, Noctor SC. Neural Progenitor Cell Terminology. Frontiers in Neuroanatomy. [Online] 2018;12. Available from: doi:10.3389/fnana.2018.00104 [Accessed: 5th November 2021]

3. Sambasivan R, Steventon B. Neuromesodermal Progenitors: A Basis for Robust Axial Patterning in Development and Evolution. Frontiers in Cell and Developmental Biology. [Online] 2021;8. Available from: doi:10.3389/fcell.2020.607516 [Accessed: 4th November 2021]

4. Tani S, Chung U, Ohba S, Hojo H. Understanding paraxial mesoderm development and sclerotome specification for skeletal repair. Experimental & Molecular Medicine. [Online] 2020;52(8): 1166–1177. Available from: doi:10.1038/s12276-020-0482-1 [Accessed: 5th November 2021]

5. Binagui-Casas A, Dias A, Guillot C, Metzis V, Saunders D. Building consensus in neuromesodermal research: Current advances and future biomedical perspectives. Current Opinion in Cell Biology. [Online] 2021;73: 133–140. Available from: doi:10.1016/j.ceb.2021.08.003 [Accessed: 6th November 2021]

6. Wymeersch FJ, Wilson V, Tsakiridis A. Understanding axial progenitor biology in vivo and in vitro. Development. [Online] 2021;148(4): dev180612. Available from: doi:10.1242/dev.180612 [Accessed: 5th November 2021]

7. Olmsted ZT, Paluh JL. Stem Cell Neurodevelopmental Solutions for Restorative Treatments of the Human Trunk and Spine. Frontiers in Cellular Neuroscience. [Online] 2021;15. Available from: doi:10.3389/fncel.2021.667590 [Accessed: 6th November 2021]

8. Dell’Anno MT, Wang X, Onorati M, Li M, Talpo F, Sekine Y, et al. Human neuroepithelial stem cell regional specificity enables spinal cord repair through a relay circuit. Nature Communications. [Online] 2018;9(1). Available from: doi:10.1038/s41467-018-05844-8 [Accessed: 7th November 2021]

9. Kajikawa K, Imaizumi K, Shinozaki M, Shibata S, Shindo T, Kitagawa T, et al. Cell therapy for spinal cord injury by using human iPSC-derived region-specific neural progenitor cells. Molecular Brain. [Online] 2020;13(1). Available from: doi:10.1186/s13041-020-00662-w [Accessed: 5th November 2021]

10. Faustino Martins J-M, Fischer C, Urzi A, Vidal R, Kunz S, Ruffault P-L, et al. Self-Organizing 3D Human Trunk Neuromuscular Organoids. Cell Stem Cell. [Online] 2020;26(2): 172-186.e6. Available from: doi:10.1016/j.stem.2019.12.007 [Accessed: 5th November 2021]

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