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Engineered biomaterials to modulate cell-cell signaling for the robust expansion of stem cells

Award Number: R01EB027171
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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Engineered biomaterials to modulate cell-cell signaling for the robust expansion of stem cells - PROJECT SUMMARY Adult stem cells hold significant therapeutic potential to treat many diseases and injuries. For example, neural progenitor cells (NPCs) are currently being investigated in over 20 clinical trials for use in a variety of indications. Despite their significant clinical relevance, we currently lack the biological mechanistic understanding to efficiently expand NPCs in vitro, even as neurospheres, while maintaining their undifferentiated, regenerative stem phenotype. Recently, 3D matrices have emerged as a tool for stem cell expansion; unfortunately, once encapsulated, NPCs commonly lose their stemness and ability to proliferate. Loss of NPC stemness is also observed in vivo throughout the aging process and in pathological disease states causing diminished ability for NPC self-renewal and biased differentiation. These phenotypic abnormalities are due in part to complex environmental changes in the stem cell niche including altered extracellular matrix biochemical and biomechanical properties. Therefore, we propose the use of a 3D in vitro hydrogel culture platform with controlled matrix biochemistry and biomechanics that will enable the exploration of previously untestable hypotheses on the mechanisms by which the surrounding cell microenvironment influences NPC maintenance, expansion, and differentiation. We will use a family of protein-engineered hydrogels to understand the impact of the matrix microenvironment on human iPSC-derived NPC (hNPC) phenotype. Specifically, we will study the role of matrix biochemical and biomechanical properties on activation of the N-cadherin signaling pathway and downstream hNPC phenotype. In Aim 1, we tune the biochemical cues presented within elastin-like protein (ELP) hydrogels to display a N-cadherin-mimetic peptide. We hypothesize that cell engagement with the artificial N-cadherin will result in downstream -catenin signaling, stemness maintenance, and enhanced symmetric proliferation compared to neurosphere controls. In Aim 2, we tune the biomechanical cues presented by the recombinant ELP hydrogels to enable dynamic matrix remodeling through viscoelastic stress relaxation. We hypothesize that dynamic matrix remodeling will result in increased cell-cell contacts, induction of cellular-based N-cadherin signaling, stemness maintenance, and enhanced symmetric proliferation compared to neurosphere controls. In Aim 3, we evaluate the hypothesis that control of specific matrix material properties to tune N-cadherin presentation and ELP hydrogel mechanics alters outside-in signal transduction that biases hNPC differentiation. The biological mechanisms underlying this process will be explored via changes in nuclear architecture (lamin expression and nuclear morphology) and epigenetics (histone modification and chromosomal organization). Further mechanistic insight will be explored using inhibitors and agonists of key mechanotransduction signaling pathways. Our engineered, modular hydrogels allow us to explore the mechanisms by which specific matrix cues regulate hNPC stem maintenance and differentiation. Given the immense regenerative potential of these cells, our findings will inform the design of a robust in vitro platform for the clinical expansion of hNPCs.


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: 2024 ( Subtotal = -$12 )
2024	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	8/26/2024	NON-COMPETING CONTINUATION	-$12
														Subtotal = -$12

Issue Date FY: 2022 ( Subtotal = $352,125 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	12/20/2021	NON-COMPETING CONTINUATION	$316,912
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	4	6/27/2022	NON-COMPETING CONTINUATION	$35,213
														Subtotal = $352,125

Issue Date FY: 2021 ( Subtotal = $345,082 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	3/18/2021	NON-COMPETING CONTINUATION	$345,082
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	3	5/27/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $345,082

Issue Date FY: 2020 ( Subtotal = $352,125 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	2/28/2020	NON-COMPETING CONTINUATION	$352,125
														Subtotal = $352,125

Issue Date FY: 2019 ( Subtotal = $352,125 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	5/28/2019	NEW	$352,125
														Subtotal = $352,125

Grand Total All Awards = $1,401,445

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Engineered biomaterials to modulate cell-cell signaling for the robust expansion of stem cells

Award Number: R01EB027171

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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