UCLA researchers from the Department of Neurobiology have developed innovative protocols to differentiate and expand spinal sensory interneurons for drug discovery and to utilize in cell replacement therapies to restore injured spinal cords.
BACKGROUND: Spinal cord injuries (SCIs) can result in the loss of controlled movement and somatosensation, the ability to perceive the environment. Surgery can resolve SCIs in some cases, but it cannot restore or replace spinal cord neurons that are already damaged. This can lead to life-long paralysis and/or loss of sensation. One potential solution to overcome this challenge is through treatments such as stem cell-based therapies, which deliver stem cells into the spinal cord to replace neurons that have been lost or injured. However, these treatments primarily focus on improving the coordinated motor function of patients, without addressing somatosensation, which is critical for patients’ quality of life. Additionally, there are technical limitations that make expanding stem cells in large quantities impractical, limiting the availability of these treatments. Furthermore, the lack of in vitro differentiation methods to help expand the stem cells also limits the ability to identify potential drug targets as alternative modes of treatment. To recover the somatosensory functions of patients with SCIs and the ability to expand stem cells for greater scaling of treatments, development of methods to generate and expand sensory spinal neurons would be invaluable for clinical and drug discovery applications.
INNOVATION: Researchers at UCLA have developed novel in vitro protocols that can direct mouse embryonic stem cells (mESCs) into all known classes of dorsal spinal sensory interneurons (dl1-dl6) (i.e. classes of neurons that receive and transmit somatosensory information from the periphery back to the central nervous system). Through transcrptomics and histology, researchers the identity of these different classes of dls and demonstrated that the dl classes mirrored their in vivo counterparts to a remarkable degree. In turn, researchers found drug-related signaling pathways present in the different dls, giving insight into potential candidate drug targets. UCLA researchers have also leveraged a specific signaling pathway to develop an innovative in vitro protocol for deriving and maintaining dls in large quantities and for long periods of time while retaining their identity. Lastly, by using a slightly altered differentiation protocol, researchers can also direct mESCs to cardiac mesodermal fates. Altogether, UCLA researchers have developed novel methods to differentiate and expand spinal sensory interneurons, creating opportunities for drug discovery and cellular replacement therapies.
POTENTIAL APPLICATIONS:
ADVANTAGES:
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mESCs can be directed into the correct complement of different types of dls
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The differentiated dls accurately resemble their in vivo counterparts
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Dl precursors can be maintained for a significant amount of time while retaining their identity
DEVELOPMENT-TO-DATE: UCLA researchers have developed in vitro methods to differentiate mESCs into dls resembling their in vivo counterparts. These differentiation protocols allow researchers to expand dls in significant quantities while retaining their identity.
Related Papers (from the inventors only):
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Gupta S., Yamauchi, K., Novitch, B.G. and S. J. Butler (2021). Derivation of dorsal spinal sensory interneurons from human pluripotent stem cells. STAR Protocols. 2:100319 10.1016/j.xpro.2021.100319
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Gupta. S., Sivaligam, D., Hain, S., Makkar, C., Sosa, E., Clark. A. and S.J. Butler. (2018). Deriving dorsal spinal interneurons from human pluripotent stem cells. Stem Cell Reports 10:1-16
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Andrews, M.G., del Castillo, L. M., Ochoa-Bolton, E., Yamauchi, K., Smogorzewski, J. and S.J. Butler. (2017). BMPs direct sensory interneuron identity in the developing spinal cord using signal-specific not morphogenic activities. eLife 6:e30647 DOI: 10.7554/eLife.30647
Keywords: Spinal cord injury, SCI, somatosenasation, stem cells, stem cell therapy, murine embryonic stem cells, mESCs, dorsal spinal interneurons, dls, mesodermal, periphery, central nervous system, transcriptomics, histology, differentiation protocols