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A Fully Patterned Human Neural Tube Model Using Microfluidics

Award Number: R01NS129850
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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A Fully Patterned Human Neural Tube Model Using Microfluidics - Project Summary A Fully Patterned Human Neural Tube Model Using Microfluidics The development of vertebrate central nervous system (CNS) begins with the formation of neural tube (NT) and its regional patterning to generate neuronal subtypes along the rostral (R)-caudal (C) and dorsal (D)- ventral (V) axes. Regional patterning of the human NT is a tightly regulated process, deviation from which can result in neurodevelopmental disorders and may lead to distinct neurological and psychiatric diseases later in life. Regional patterning of the human NT remains incompletely understood due to limited access to human embryonic tissues. Animal models have been instrumental in understanding the development of human CNS and associated disorders. However, they are limited in revealing some fundamental aspects of development, genetics, pathology, and disease mechanisms that are unique to humans. Stem cell-based in vitro models of human nervous system development, including neural organoids and bioengineered NT development models, are emerging as promising experimental tools. However, none of the current stem cell-based neural development models is capable of recapitulating neural patterning along two orthogonal axes in a 3D tubular geometry, the hallmark of NT patterning in vivo. Furthermore, the existing neural development models only recapitulate certain aspects of the development of either human brain or spinal cord regions but not both. In our preliminary study, we have successfully leveraged the developmental potential and self- organizing property of human pluripotent stem cells (hPSCs) in conjunction with microfluidics to develop the first of its kind, synthetic, fully patterned human NT model. Using this microfluidic platform, exogenous morphogen gradients along two orthogonal axes can be established to achieve regional patterning of the microfluidic human NT-like structure along both the R-C and D-V axes, in both brain-like and spinal cord-like regions. This microfluidic patterned human NT-like structure exhibits many hallmarks of NT development, including a tubular geometry, a single continuous central lumen enclosing by neuronal progenitor cells, patterned expression of canonical R-C and D-V regional markers including HOX genes, and the emergence of neural mesodermal progenitors and the isthmic organizer. Thus, the development of the microfluidic human NT-like structure closely mimics NT development, offering for the first time an in vivo-like tissue architecture with consistent spatiotemporal cell differentiation and organization. The goal of this R01 research is to develop this exciting microfluidic human NT-like model (Aim 1) and leverage its technical advantages to study the roles of different exogenous morphogen signals in neural patterning (Aim 2 & 3). Genetic perturbations and lineage tracing assays will be conducted to study human neural mesodermal progenitor development (Aim 2). In Aim 3 we further aim to achieve D-V patterned human NT-like structures with either forebrain or spinal cord identities and use these structures to recapitulate interregional cellular interactions and excitation-to-inhibition interplays during cortical development.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $523,443 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/19/2026	NON-COMPETING CONTINUATION	$523,443
														Subtotal = $523,443

Issue Date FY: 2025 ( Subtotal = $523,443 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/28/2025	NON-COMPETING CONTINUATION	$523,443
														Subtotal = $523,443

Issue Date FY: 2024 ( Subtotal = $507,741 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/30/2024	NON-COMPETING CONTINUATION	$507,741
														Subtotal = $507,741

Issue Date FY: 2023 ( Subtotal = $523,443 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/14/2023	NEW	$523,443
														Subtotal = $523,443

Grand Total All Awards = $2,078,070

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A Fully Patterned Human Neural Tube Model Using Microfluidics

Award Number: R01NS129850

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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