Flash-Drive Sized Chip Could Lead New ALS Research

In an article published last week in the journal Stem Cell Reports, researchers Clive Svendsen, PhD and Samuel Sances of the Cedars-Sinai Board of Governors Regenerative Medicine Institute in Los Angeles note that spinal neuron development can be initiated by the human brain’s tiniest blood vessels.¹

Organ-Chip, which has been developed to recreate human biology on a microchip, has been used to track living tissues on a chip, and provided researchers a novel technique to study the disease processes in amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.

The findings could potentially provide insights into how ALS and other neurological diseases cultivate.

"Until now, people thought these blood vessels just delivered nutrients and oxygen, removed waste and adjusted blood flow. We showed that beyond plumbing, they are genetically communicating with the neurons," said Sances, a postdoctoral fellow and first author of the study, in a press release.²

In their work, Drs Svendsen and Sances took human skin cell samples and genetically reprogrammed them into induced pluripotent stem cells (iPSCs) that can be turned into different cell types in the body; in this instance, they turned iPSCs into spinal motor neurons. Spinal motor neurons are the cells that die in ALS, and are characteristically responsible for connecting to muscles to signal movement.

To study this interaction and influence of microculture, the researchers copied both spinal motor neurons and BMECs from human induced pluripotent stem cells and observed increased calcium transient function and Chip-specific gene expression in Organ-Chips compared with 96-well plates.

The study, “Human iPSC-Derived Endothelial Cells and Microengineered Organ-Chip Enhance Neuronal Development,” concluded that: iPSC-derived neuronal and vascular tissue interact in Organ-Chip; chip culture enhances neuron function and signaling; iPSC-derived vasculature affects neuron development and neuron-vasculature pathways; and brain microvascular endothelial cells (BMECs) co-cultured on Chip co-culture activate in vivo spinal cord developmental genes.

“Brain microvascular endothelial cells (BMECs) share common signaling pathways with neurons early in development, but their contribution to human neuronal maturation is largely unknown,” it was noted in the study. “Seeding BMECs in the Organ-Chip led to vascular-neural interaction and specific gene activation that further enhanced neuronal function and in vivo-like signatures. The results show that the vascular system has specific maturation effects on spinal cord neural tissue, and the use of Organ-Chips can move stem cell models closer to an in vivo condition.”

With these findings, the hope is that the Organ-Chip can soon be applied to ALS research as quickly as possible. It is currently being used in a large study designed to seek out new biomarkers and disease targets for therapy development. “Importantly, the intact nature of the blood vessel compartment could enable rapid drug development by studying the effects of delivering experimental therapeutics through blood vessels into neural tissue,” said Sances in an interview with the ALS Association.³

The research is part of a larger collaboration between Cedars-Sinai and Emulate Inc., the Patient-on-a-Chip program, which aims to predict which treatments would be most effective for specific diseases based entirely on a patient’s genetic makeup and disease variant.

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References:

1. Human iPSC-Derived Endothelial Cells and Microengineered Organ-Chip Enhance Neuronal Development. Sances, S., et al. Stem Cell Reports. Published online: March 22, 2018. DOI: https://doi.org/10.1016/j.stemcr.2018.02.012
2. Brain’s Tiniest Blood Vessels Trigger Spinal Motor Neurons to Develop [news release]. Los Angeles, CA: Cedars-Sinai; March 23, 2018. https://www.cedars-sinai.edu/About-Us/News/News-Releases-2018/Brains-Tiniest-Blood-Vessels-Trigger-Spinal-Motor-Neurons-to-Develop.aspx/. Accessed April 5, 2018.
3. Organ-Chip Technology Can Be Applied to Understand ALS Disease Pathways. Washington, D.C.: The ALS Association; March 27, 2018. https://alsadotorg.wordpress.com/2018/03/27/organ-chip-technology-can-be-applied-to-understand-als-disease-pathways/. Accessed April 5, 2018.