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Abstract
The ability to reliably repair spinal cord injuries (SCI) will be one of the greatest human achievements realized in regenerative medicine. Until recently, the cellular path to this goal has been challenging. However, as detailed developmental principles are revealed in mouse and human models, their application in the stem cell community brings trunk and spine embryology into efforts to advance human regenerative medicine. New models of posterior embryo development identify neuromesodermal progenitors (NMPs) as a major bifurcation point in generating the spinal cord and somites and is leading to production of cell types with the full range of axial identities critical for repair of trunk and spine disorders. This is coupled with organoid technologies including assembloids, circuitoids, and gastruloids. We describe a paradigm for applying developmental principles towards the goal of cell-based restorative therapies to enable reproducible and effective near-term clinical interventions.
Highlights
For the entirety of recorded human medical history, injury to the trunk and spinal cord has carried with it the potential for untreatable loss of functional modalities, and severely compromised quality and duration of life (Silva et al, 2014)
The first decade of the 21st century has seen a new revolution in human developmental neurotechnologies that would not be possible without mouse and human stem cell advances that continue to accelerate (Figure 5; Thomson et al, 1998; Takahashi and Yamanaka, 2006; Cong et al, 2013; Mayr et al, 2019)
For human therapies of the trunk and spine (Figures 4, 5), information arising from developmental neurotechnologies, including embryology, can be analyzed to inform and improve treatments beyond trauma
Summary
For the entirety of recorded human medical history, injury to the trunk and spinal cord has carried with it the potential for untreatable loss of functional modalities, and severely compromised quality and duration of life (Silva et al, 2014). Wnt agonism by the small molecule CHIR 99021 and soluble recombinant FGF signaling are necessary and sufficient to produce high-yield NMPs. generation sequencing technologies are revealing new human temporal information by applying strategies that enable lineage tracing of cell identity during differentiation in vitro and comparing this to transitional developmental events (morphological and functional) to capture evolving gene regulatory networks (Figure 2B; Gouti et al, 2014, 2017; Verrier et al, 2018). The in vivo action of a segmentation clock associated with waves of somite production was recapitulated in vitro using human stem cells (Figure 3D) (Diaz-Cuadros et al, 2020; Matsuda et al, 2020) Together, these multiple important refinements in differentiation protocols enable us to achieve the production of regionally-specified neuronal and mesodermal subtypes. Strategies aimed at achieving a closer adherence to the developmental origin of the PNS apply NCC intermediates from hPSCs to generate diverse sensory neuronal subtypes found within the dorsal root ganglion (Denham et al, 2015; Alshawaf et al, 2018). Alshawaf et al (2018) optimized the temporal addition of inhibitors and soluble ligands to produce sensory neurons that respond to noxious, thermal, and mechanical stimuli
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