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Identifying the precursor to hematopoietic stem cells in the mouse embryo and improving its engraftment upon transplantation

Award Number: R21CA224022
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY There is a fundamental gap in understanding how hematopoietic stem cells (HSCs) first emerge during embryonic development. This includes 1) the identity of the HSC precursor (pre-HSCs), and 2) why HSCs (but not pre-HSCs) are able to seed the bone marrow and engraft upon transplantation into adult hosts. Without first addressing these questions, the potential to apply that knowledge to improve the engraftment of HSCs, or pluripotent stem cell (PSC) derived HSCs, upon transplantation as treatments for blood diseases will remain unrealized. The long-term goal of this research team is to better understand the molecular mechanisms that regulate HSC emergence and maturation in the embryo. The overall objective in this application is to identify pre-HSCs in the embryo and determine why they cannot engraft in adults. The central hypothesis is that an embryonic population called “eKLS” contains pre-HSCs that cannot engraft into bone marrow due to the absence of homing molecules on their surface, such as the chemokine receptor Cxcr4. This hypothesis has been formulated on the basis of two lines of preliminary data: First, that sorted eKLS cells can engraft and become HSCs when transplanted into neonatal mice, and second, that eKLS cells lack expression of Cxcr4 and other homing factors. The rationale for the proposed research is that, once pre-HSCs have been identified, they can be compared to adult HSCs to better understand what factors are critical for engraftment. This hypothesis will be tested by pursuing two specific aims: 1) To determine whether eKLS cells or another embryonic cell gives rise to HSCs in vivo, and 2) To determine whether the ability to respond to Cxcr4/Cxcl12 signaling distinguishes pre-HSCs from HSCs. Under the first aim, the neonatal transplantation system will be used to identify which embryonic populations and in which embryonic tissues contain pre-HSCs. Under the second aim, Cxcr4 and other homing factors will be expressed in eKLS cells to determine whether they can imbue those cells with the ability to engraft in adult recipients. The research proposed in this application is conceptually innovative because it focuses on the differences between HSCs and their immediate precursors as a way to understand how HSCs emerge and mature during embryonic development. The proposed research is significant because it could lead to breakthroughs in the engraftabilty of HSCs and/or PSC-derived HSCs upon transplantation. This could dramatically improve the safety and efficacy of HSC transplantation as a treatment for nearly any blood disease.


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 = $0 )
2024	2020	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Treatment Research	000	2	10/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Treatment Research	000	2	12/14/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $192,389 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Treatment Research	000	2	12/5/2019	NON-COMPETING CONTINUATION	$173,150
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Treatment Research	001	2	1/13/2020	NON-COMPETING CONTINUATION	$19,239
														Subtotal = $192,389

Issue Date FY: 2019 ( Subtotal = $159,308 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Treatment Research	000	1	1/10/2019	NEW	$159,308
														Subtotal = $159,308

Grand Total All Awards = $351,697

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Identifying the precursor to hematopoietic stem cells in the mouse embryo and improving its engraftment upon transplantation

Award Number: R21CA224022

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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