Stem cells can be viewed as having therapeutic potential either when delivered exogenously or when endogenous cells respond to injury. The central premise of this proposal is that successful therapeutic effect of either is dependent upon the interaction of the stem cells with a complex microenvironment. The regulatory components of this microenvironment function as an integrated system, providing a niche that modulates stem cell fate in response to physiologic stimuli. Yet this aspect of cell based therapy is often ignored. We have previously shown that understanding some components of the hematopoietic stem cell niche {the osteoblast and its response to hormonal stimulation) can lead to a strategy for improving stem cell outcomes in a physiologically meaningful context (parathyroid hormone stimulation to improve bone marrow transplantation). These studies in mice provided proof of principle that understanding and manipulating the stem cell niche can result in a therapeutic result relevant to human disease. Our intent here is to extend this novel, cell based approach to therapy development along two lines. First, to deepen understanding of the components of the hematopoietic stem cell niche and assess how these components function in vivo. Second, to convert this understanding derived from mouse models to clinical trials in humans with hematologic disease. Our program is therefore composed of four main projects, two laboratory based and two clinically based. The main thrust of these is: Project 1: define Wnt signaling effects on osteoblast biology led by Dr. Henry Kronenberg; Project 2: determine the impact of multiple constituents of the bone marrow niche on stem cell function led by Dr. David Scadden; Project 3: convert murine models to human use through chimeric animal studies, engagement of cell manipulation and clinical trial teams for two specific niche-related trials led by Dr. Gregor Adams; Project 4: test manipulation of the niche as a strategy to improve stem cell harvesting or stem cell engraftment in three clinical trials using a clinical trial consortium led by Dr. Karen Ballen. These will be supported by three cores. Success of the proposal will provide rationale for continued development of a novel, niche-based approach to cell therapies for multiple disease entities. Further, it will create infrastructure needed to rapidly move such therapies from mouse model to pre-clinical assessment to human clinical trial.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HL081030-03
Application #
7282059
Study Section
Special Emphasis Panel (ZHL1-CSR-N (M1))
Program Officer
Thomas, John
Project Start
2005-09-30
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
3
Fiscal Year
2007
Total Cost
$2,189,425
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Brunstein, Claudio G; Cutler, Corey S; DeFor, Todd E et al. (2017) Matching at Human Leukocyte Antigen-C Improved the Outcomes after Double Umbilical Cord Blood Transplantation for Recipients of Two to Four of Six Human Leukocyte Antigen-Matched Grafts. Biol Blood Marrow Transplant 23:126-133
Nikiforow, Sarah; Li, Shuli; Snow, Karen et al. (2017) Lack of impact of umbilical cord blood unit processing techniques on clinical outcomes in adult double cord blood transplant recipients. Cytotherapy 19:272-284
Li, L; Kim, H T; Nellore, A et al. (2014) Prostaglandin E2 promotes survival of naive UCB T cells via the Wnt/?-catenin pathway and alters immune reconstitution after UCBT. Blood Cancer J 4:e178
Cutler, Corey; Multani, Pratik; Robbins, David et al. (2013) Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood 122:3074-81
Ballen, Karen; Mendizabal, Adam M; Cutler, Corey et al. (2012) Phase II trial of parathyroid hormone after double umbilical cord blood transplantation. Biol Blood Marrow Transplant 18:1851-8
Sanchez-Aguilera, Abel; Lee, Yun-Jung; Lo Celso, Cristina et al. (2011) Guanine nucleotide exchange factor Vav1 regulates perivascular homing and bone marrow retention of hematopoietic stem and progenitor cells. Proc Natl Acad Sci U S A 108:9607-12
Lo Celso, Cristina; Lin, Charles P; Scadden, David T (2011) In vivo imaging of transplanted hematopoietic stem and progenitor cells in mouse calvarium bone marrow. Nat Protoc 6:1-14
Raaijmakers, Marc H G P; Mukherjee, Siddhartha; Guo, Shangqin et al. (2010) Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464:852-7
Guo, Jun; Liu, Minlin; Yang, Dehong et al. (2010) Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab 11:161-71
Ballen, Karen K; Cutler, Corey; Yeap, Beow Y et al. (2010) Donor-derived second hematologic malignancies after cord blood transplantation. Biol Blood Marrow Transplant 16:1025-31

Showing the most recent 10 out of 20 publications