Recent reports have raised the possibility that use of adult stem cells from bone marrow may provide dramatic new therapies for both acute and chronic cardiac diseases. However, to develop a safe and effective therapy with adult stem cells, a number of problems and issues must be resolved. We will focus our attention on the adult stem cells from bone marrow referred to as either mesenchymal stem cells or marrow stromal cells (MSCs). The cells have several advantages over other stem cells in that they can readily be isolated from a patient to be treated, they are not tumorogenic, they are multipotential for differentiation into many cell phenotypes, and they have shown a remarkable ability to home to sites of tissue injury and repair the injury. We will first thoroughly characterize distinct subclasses of MSCs that we have recently identified and that apparently include the earliest progenitors and the most multipotential cells in standard cultures of MSCs. We will then compare standardized preparations of the cells for engraftment and differentiation first in a simple ex vivo co-culture system with cardiac cells, and then in rat in vivo models for acute and chronic ischemic damage to heart.
The Specific Aims are: (1) Further characterize the special subclass of stem-like cells that we have recently isolated from cultures of MSCs and that have unusually long telomeres and propagate more rapidly than parallel samples of MSCs. We will test the hypothesis that the cells are pre-RS cells, i.e. precursors of the rapidly self-renewing cells (RS cells) that we previously identified as a sub-population of early progenitors in standard cultures of MSCs. (2) Use an ex vivo co-culture system to compare the ability of the putative pre-RS cells, RS cells, mMSCs, and marrow mononuclear cells, to repair hypoxic damage to cardiac cells either through direct differentiation of the cells or through cell fusion. (3) Isolate and characterize putative pre-RS ceils, RS cells, mMSCs, and mononuclear cells from rat bone marrow for testing in in vivo models of cardiac ischemia in Specific Aim 4. (4) Determine the ability of rMSCs, mMSCs, pre-RS, RS, and unfractionated mononuclear cells from rat marrow to engraft into and produce functional improvement and reduce damage in rat models of acute myocardial infarction (ischemia-reperfusion) and coronary arteriogenesis (intermittent repetitive ischemia).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073755-03
Application #
6920728
Study Section
Special Emphasis Panel (ZHL1-CSR-J (M2))
Program Officer
Lundberg, Martha
Project Start
2003-07-15
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$438,419
Indirect Cost
Name
Tulane University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Mohammadipoor, Arezoo; Lee, Ryang Hwa; Prockop, Darwin J et al. (2016) Stanniocalcin-1 attenuates ischemic cardiac injury and response of differentiating monocytes/macrophages to inflammatory stimuli. Transl Res 177:127-142
Prockop, Darwin J; Oh, Joo Youn (2012) Medical therapies with adult stem/progenitor cells (MSCs): a backward journey from dramatic results in vivo to the cellular and molecular explanations. J Cell Biochem 113:1460-9
Ohkouchi, Shinya; Block, Gregory J; Katsha, Ahmed M et al. (2012) Mesenchymal stromal cells protect cancer cells from ROS-induced apoptosis and enhance the Warburg effect by secreting STC1. Mol Ther 20:417-23
Mao, Jeremy J; Robey, Pamela G; Prockop, Darwin J (2012) Stem cells in the face: tooth regeneration and beyond. Cell Stem Cell 11:291-301
Prockop, Darwin J; Kota, Daniel J; Bazhanov, Nikolay et al. (2010) Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs). J Cell Mol Med 14:2190-9
Uccelli, Antonio; Prockop, Darwin J (2010) Why should mesenchymal stem cells (MSCs) cure autoimmune diseases? Curr Opin Immunol 22:768-74
Bartosh, Thomas J; Ylöstalo, Joni H; Mohammadipoor, Arezoo et al. (2010) Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties. Proc Natl Acad Sci U S A 107:13724-9
Belmadani, Souad; Matrougui, Khalid; Kolz, Chris et al. (2009) Amplification of coronary arteriogenic capacity of multipotent stromal cells by epidermal growth factor. Arterioscler Thromb Vasc Biol 29:802-8
Block, Gregory J; Ohkouchi, Shinya; Fung, France et al. (2009) Multipotent stromal cells are activated to reduce apoptosis in part by upregulation and secretion of stanniocalcin-1. Stem Cells 27:670-681
Lee, Ryang Hwa; Seo, Min Jeong; Pulin, Andrey A et al. (2009) The CD34-like protein PODXL and alpha6-integrin (CD49f) identify early progenitor MSCs with increased clonogenicity and migration to infarcted heart in mice. Blood 113:816-26

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