The central tenant of this proposal is that mesenchymal cells are necessary participants in tissue development, maintenance and repair and will be required for realization of the full potential of reprogrammed cells in regenerative medicine. Efforts to exploit the advance of cell reprogramming will depend upon in-depth understanding of how cell state is specified, how the cells organize into complex patterns and how heterotypic cells interrelate during times of physiologic stress. A cell autonomous perspective on these processes is inadequate and can be complemented by full elucidation of the contributory role tissue specific mesenchymal cells play. Based on lessons from development, it is clear that mesenchymal cells are fundamental for establishing the organization of a tissue, altering the proliferation, differentiation and patterning of specific cell types. Yet mesenchymal populations remain enigmatic in terms of their complexity, their lineage relationships and the regulatory pathways that mediate their functions. This proposal seeks to address this deficiency by assembling a group of investigators with complementary strengths who have a record of highly productive and collaborative science. The following specific aims will be addressed: 1. define mesenchymal lineages comprising organ stroma in marrow, lung and heart. Previously defined methods of isolating, molecularly and functionally characterizing and anatomically localizing cell populations in vivo will be applied and comparisons performed 2. Define how the microenvironment accomplishes its regulatory control by modifying the interactions of stromal cells and progenitor cells. Interactions between stromal and progenitor cell populations will be modified by genetic and small molecule manipulations. 3. Interact with other Consortium participants to evaluate the ability of stromal constituents to affect lineage differentiation and progenitor function in the context of induced pluripotent cells (iPS). Successful accomplishment of these aims will provide a complement to progenitor focused aspects of the Consortium and thereby enable a tissue-based approach to regenerative medicine.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL100402-06
Application #
8661233
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S1))
Program Officer
Blaisdell, Carol J
Project Start
2009-09-30
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
$1,206,710
Indirect Cost
$209,175
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Painter, Michio W; Brosius Lutz, Amanda; Cheng, Yung-Chih et al. (2014) Diminished Schwann cell repair responses underlie age-associated impaired axonal regeneration. Neuron 83:331-43
Scadden, David T (2014) Nice neighborhood: emerging concepts of the stem cell niche. Cell 157:41-50
Saez, Borja; Ferraro, Francesca; Yusuf, Rushdia Z et al. (2014) Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning. Blood 124:2937-47
Lau, Allison N; Curtis, Stephen J; Fillmore, Christine M et al. (2014) Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis. EMBO J 33:468-81
Wu, Juwell W; Runnels, Judith M; Lin, Charles P (2014) Intravital imaging of hematopoietic stem cells in the mouse skull. Methods Mol Biol 1185:247-65
Sinha, Manisha; Jang, Young C; Oh, Juhyun et al. (2014) Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344:649-52
Ksander, Bruce R; Kolovou, Paraskevi E; Wilson, Brian J et al. (2014) ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature 511:353-7
Lee, Joo-Hyeon; Bhang, Dong Ha; Beede, Alexander et al. (2014) Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell 156:440-55
Xu, Chunxiao; Fillmore, Christine M; Koyama, Shohei et al. (2014) Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 25:590-604
Kalaitzidis, Demetrios; Scadden, David T (2014) Tic-TACs: refreshing hair growth. Cell 157:769-70

Showing the most recent 10 out of 35 publications