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Gradient biomaterials to investigate niche regulation of hematopoiesis

Award Number: R01DK099528
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2014
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Gradient biomaterials to investigate niche regulation of hematopoiesis - ABSTRACT The hematopoietic system offers an ideal biological system to develop tools to study how dynamic matrix, metabolic, and cellular selection pressures influence stem cell fate. Hematopoiesis is the process where the body’s blood and immune cells are generated from a small number of hematopoietic stem cells (HSCs). HSC quiescence, self-renewal, and differentiation take place in, and are regulated by, unique regions of the bone marrow termed niches. HSCs are also the functional unit of therapeutic bone marrow transplants following myeloablative therapies. A major goal of the hematology community is to selectively expand HSCs without sacrificing a subpopulation of quiescent, long-term repopulating HSCs required for life-long hematopoiesis. Yet while the marrow is known to change substantially across the lifespan, studies of the influence of niche remodeling on HSC behavior are in their infancy. The long-term goal of this Stimulating Hematology Investigation New Endeavors (SHINE) project is to advance tissue engineering platforms to achieve HSC expansion without exhaustion. In the previous funding period (R01DK099528) we established a tissue engineering ecosystem to examine the coordinated impact of niche-inspired biophysical signals on HSC fate. We developed microfluidic tools for extended culture of primary murine HSC in miniaturized gelatin hydrogels containing marrow-inspired gradients of stiffness, niche cells, and soluble vs. immobilized biomolecules We showed the kinetics of HSC- niche cell crosstalk can be manipulated via biomaterial design to enhance retention of quiescent HSCs. Mesenchymal stem cells (MSCs) within the marrow are increasingly believed to dynamically remodel the niche and provide powerful signals to influence HSC fate. Hence, the objective of our renewal is to use an innovative granular biomaterial to investigate the coordinated action of MSC remodeling and hypoxic stress on functional changes in HSC activity. We hypothesize the mosaic nature of the bone marrow can be replicated as jammed assemblies of cell-laden hydrogel microdroplets. We will create granular hydrogels from MSC and HSC microdroplets to trace the consequences of matrix remodeling, metabolic constraint, and MSC-HSC crosstalk on HSC fate. To accomplish this goal we will first establish an engineered model of MSC-mediated niche remodeling (Aim 1). We will define shifts in HSC-MSC crosstalk under hypoxia (Aim 2). And we will evaluate a mosaic granular hydrogel model of the multicellular marrow (Aim 3). Granular hydrogels provide the technical basis for creating mosaic niche analogs necessary to study remodeling mediated effects on HSC activity. The well- characterized murine hematopoietic system provides a rigorous framework to evaluate ex vivo regulatory processes in niches whose rarity and complexity limit direct in vivo study. Consistent with score-driving criteria of the SHINE program, we will develop essential tools to rigorously assess how dynamic processes of matrix remodeling and HSC-niche cell crosstalk inform HSC stemness that is directly relevant to the NIDDK mission.


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: 2025 ( Subtotal = $574,828 )
2025	2025	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	5/28/2025	NON-COMPETING CONTINUATION	$574,828
														Subtotal = $574,828

Issue Date FY: 2024 ( Subtotal = $548,824 )
2024	2024	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	5/21/2024	NON-COMPETING CONTINUATION	$548,805
2024	2023	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	2/9/2024	COMPETING CONTINUATION	$19
														Subtotal = $548,824

Issue Date FY: 2023 ( Subtotal = $601,729 )
2023	2023	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	8/28/2023	COMPETING CONTINUATION	-$33,375
2023	2023	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	7/11/2023	COMPETING CONTINUATION	$635,104
														Subtotal = $601,729

Issue Date FY: 2022 ( Subtotal = -$19 )
2022	2018	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/29/2021	NON-COMPETING CONTINUATION	-$19
														Subtotal = -$19

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/31/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $334,718 )
2018	2018	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/30/2018	NON-COMPETING CONTINUATION	$334,718
														Subtotal = $334,718

Issue Date FY: 2017 ( Subtotal = $335,015 )
2017	2017	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/8/2017	NON-COMPETING CONTINUATION	$335,015
														Subtotal = $335,015

Issue Date FY: 2016 ( Subtotal = $335,305 )
2016	2016	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/2/2016	NON-COMPETING CONTINUATION	$335,305
														Subtotal = $335,305

Issue Date FY: 2015 ( Subtotal = $335,585 )
2015	2015	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/29/2015	NON-COMPETING CONTINUATION	$335,585
														Subtotal = $335,585

Issue Date FY: 2014 ( Subtotal = $335,859 )
2014	2014	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/14/2014	NEW	$335,859
														Subtotal = $335,859

Grand Total All Awards = $3,401,844

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Gradient biomaterials to investigate niche regulation of hematopoiesis

Award Number: R01DK099528

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2014

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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