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Identification of unique nitric oxide-expressing hematopoietic stem cells and their special vascular niche

Award Number: R01DK121889
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Abstract Hematopoietic stem cells (HSCs) reside in the regulatory microenvironment within the bone marrow (BM), termed the niche. Despite extensive research efforts made over the past decades, cellular constituents and locations of the HSC niche have remained controversial. While early studies suggested that HSCs are adjacent to osteoblasts on the bone surface, a growing amount of more recent evidence indicate that HSCs are rather adjacent to sinusoidal vessels in the central marrow; some other showed HSCs are near BM arteries. These conflicting observations may be explained by the heterogeneity of HSCs and the niche, as well as the paucity of markers to identify HSC subsets in the histological analysis. This project focuses on proposing most primitive HSCs among others, and their niche. The overall hypothesis to be tested is that nitric oxide (NO) identifies unprecedented HSCs with distinctly high self-renewing and reconstituting potential. We further hypothesize that these NO+ HSCs are regulated by unique transitional vessels which connect arteries to sinusoidal vessels, while NO- HSCs with a relatively limited self-renewing potential are adjacent to sinusoidal veins. This hypothesis is based on the following preliminary data. We showed that, within CD150+CD48+cKit+Sca1+Lin- HSCs, there was a quiescent population (5-10%) with high expression levels of NO and CD200 receptors (CD200R). These NO+CD200Rhigh HSCs exhibited high blood reconstituting potential which was further increased by serial transplant, while NO- HSCs' reconstituting potential was relatively limited and abolished by serial transplant. This observation suggest NO+ HSCs possess a distinctly high self-renewal and reconstituting potential. Moreover, NO+ HSCs were adjacent to transitional vessels, while NO- HSCs were adjacent to sinusoids which did not express cilia or CD200. To further bring mechanistic insights into NO+ HSCs and their niche and to promote clinical translation of our basic findings, we will pursue the following aims. In Aim 1, we will seek to characterize NO+ HSCs' self-renewal, reconstituting potential and molecular features, and elucidate their intrinsic regulatory mechanisms of NO+ HSCs, by using the combination of single cell RNA sequencing, transplantation assay, genetic deletion, and in vivo microscopy tracking of symmetric or asymmetric division of photolabeled individual HSCs. In Aim 2, we will elucidate NO+ HSCs' locations and extrinsic regulatory mechanisms. We will validate localization of NO+ HSCs to transitional vessels by performing deep whole-mount 2-photon BM imaging of novel HSC-reporter mice. We will further elucidate roles of transitional vessels' CD200 and cilia in HSC regulation and protection from radiation stress. We will finally investigate therapeutic potential of CD200R agonist treatment to mitigate post-irradiation hematopoiesis failure. Completion of the project may address the controversy about the niche location by proposing unprecedented primitive HSCs and its niche. Successful studies will further identify cilia-CD200/CD200R-NO axis as new HSC regulators, leading to novel treatments for hematopoiesis failure.


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: 2023 ( Subtotal = $459,692 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/27/2023	NON-COMPETING CONTINUATION	$459,692


Issue Date FY: 2022 ( Subtotal = $432,962 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/1/2022	NON-COMPETING CONTINUATION	$43,300
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/3/2022	NON-COMPETING CONTINUATION	$389,662


Issue Date FY: 2021 ( Subtotal = $344,792 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	8/27/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$343,626
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/27/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$344,792
2021	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/19/2021	NEW	$0
2021	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	8/27/2021	NEW	-$343,626


Issue Date FY: 2020 ( Subtotal = $425,543 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/20/2020	NEW	$425,543


Grand Total All Awards = $1,662,989

Sum of Action Amount is $1,662,989;

Grand Total = $1,662,989

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Identification of unique nitric oxide-expressing hematopoietic stem cells and their special vascular niche

Award Number: R01DK121889

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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