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Biomechanical Stimulation of Hemogenic Endothelial Cells to Develop Clinical-Grade Hematopoietic Stem Cells

Award Number: R01HL131645
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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¿ DESCRIPTION (provided by applicant): The therapeutic use of hematopoietic stem cell (HSC) transplantation for inherited or acquired blood diseases is often restricted due to the difficulty with finding HLA-matched donors and immunologic intolerance between donor and recipient. Therefore, there is a critical need to identify new methods to generate high throughput, clinical-grade functional HSCs from human tissues. The objective of this application is to analyze novel cell-extrinsic mechanisms that stimulate the developmental transition from hemogenic endothelial cells to HSCs. We recently established that functional HSCs emerge in the cdh5-deleted zebrafish embryos, despite an impaired blood circulation. These findings led us to investigate shear-stress independent biomechanical mechanisms stimulating endothelial to HSC transition. Using echocardiography, micro-angiography, 3D Doppler, and confocal imaging, we demonstrate that heartbeat mediated pulse-pressure, and thus circumferential stretch stimulates HSC formation. Pharmacological inhibition of stretch-activated ion channels further reduced HSC formation. We, therefore, hypothesize that pulse-pressure mediated circumferential stretch stimulates the transition of endothelial cells to HSCs by stimulating stretch-activated ion channels. We will use advances in organ-in-a-dish and cell-engineering to recapitulate in situ circumferential stretch conditions on murine hemogenic endothelial cells. Since the silent-heart (tnnt2, sih)-silenced embryos lack heartbeat and blood circulation, we will also investigate if pharmacological stimulation of stretch-activated ion channels could rescue hematopoietic deficiency in the sih-silenced embryos. In addition, we will use transgenic zebrafish, ex vivo mouse embryo and explant culture methods, as well as confocal imaging to analyze how stimulation of stretch activated ion channels, Trpv4 and/or Piezo1, influences the emergence of functional HSCs. Our aims will establish a new conserved cell-extrinsic role and mechanisms of circumferential stretch during HSC formation. Identification of new factors stimulating hemogenic properties of endothelium would expedite the development of endothelial cells as a source of HSCs for the treatment of human blood diseases.


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: 2022 ( Subtotal = $0 )
2022	2017	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	9/26/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = -$238,017 )
2020	2019	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Blood Diseases and Resources Research	001	4	9/9/2020	NON-COMPETING CONTINUATION	-$238,017
2020	2019	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Blood Diseases and Resources Research	000	4	3/6/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = -$238,017

Issue Date FY: 2019 ( Subtotal = $380,000 )
2019	2019	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Blood Diseases and Resources Research	004	4	4/16/2019	NON-COMPETING CONTINUATION	$380,000
2019	2018	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Blood Diseases and Resources Research	003	3	2/7/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$752
2019	2018	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Blood Diseases and Resources Research	001	3	11/6/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$196
2019	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	11/6/2018	NON-COMPETING CONTINUATION	-$196
2019	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	002	2	2/7/2019	NON-COMPETING CONTINUATION	-$752
														Subtotal = $380,000

Issue Date FY: 2018 ( Subtotal = $380,000 )
2018	2018	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Blood Diseases and Resources Research	001	3	9/9/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$380,000
2018	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	9/6/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $380,000

Issue Date FY: 2017 ( Subtotal = $428,870 )
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	4/1/2017	NON-COMPETING CONTINUATION	$428,870
														Subtotal = $428,870

Issue Date FY: 2016 ( Subtotal = $428,870 )
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	4/15/2016	NEW	$428,870
														Subtotal = $428,870

Grand Total All Awards = $1,379,723

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Biomechanical Stimulation of Hemogenic Endothelial Cells to Develop Clinical-Grade Hematopoietic Stem Cells

Award Number: R01HL131645

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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