Though many have demonstrated that adult stem cells have broad regenerative capacity in a variety of non-hematopoietic tissues, there is no information available on the molecular mechanism(s) by which adult stem cells migrate to sites other than bone marrow. To exit the vascular compartment, all circulating cells must first bind to the endothelium at the target tissue. The key initial adhesive interactions between cells in blood and endothelium are generally described as """"""""rolling"""""""", whereby the fast moving cells in flow begin to """"""""brake"""""""" on the endothelial surface. This process is mediated by leukocyte """"""""homing receptors"""""""" which consist of molecules specialized for rolling interactions such as L-selectin, PSGL-1, CD44, and the integrins VLA-4, LFA-1 and alpha4beta7. While much is known about the role(s) of these molecules in regulating mature leukocyte trafficking and the migration of human CD34+ hematopoietic progenitor cells into bone marrow, virtually nothing is known about the expression and activity of these molecules as they relate to migration of human adult stem cells to non-hematopoietic sites. We hypothesize that to achieve adequate tissue delivery of infused adult stem cells for regeneration of damaged organs requires that one or more of the homing receptors on adult stem cells be functionally intact and, moreover, that the relative expression/activity of these molecules will determine in part the capacity of the cells to emigrate to relevant non-hematopoietic tissues. In this proposal, we focus our studies on adult stem cells residing in human bone marrow, as this source provides the most accessible and quantitatively greatest amount of adult stem cells for future clinical applications.
We aim to define the profile of expression and the functional capabilities of known homing receptors on defined populations of human bone marrow-derived adult stem cells including hematopoietic stem cells (HSCs), mesenchymal stem cells (MSC) and multipotential adult progenitor cells (MAPC). Moreover, to determine whether stem cells express novel homing receptors, we will utilize newly developed technology in our laboratory to examine the full spectrum of membrane molecules that can function as mediators of binding interactions under shear conditions. Based on information derived from these studies, we will analyze human adult stem cell-human endothelial interactions and the migration of human adult stem cells to non-hematopoietic tissue using an in vivo model system of human skin transplanted onto immunodeficient mice. It is anticipated that the results of these studies will guide the development of strategies to achieve high efficiency delivery of human adult stem ceils from the vasculature into target organ(s) for clinical applications of regeneration therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073714-04
Application #
7090660
Study Section
Special Emphasis Panel (ZHL1-CSR-J (M2))
Program Officer
Berberich, Mary Anne
Project Start
2003-07-11
Project End
2007-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$578,945
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Sackstein, Robert (2016) Fulfilling Koch's postulates in glycoscience: HCELL, GPS and translational glycobiology. Glycobiology 26:560-70
Merzaban, Jasmeen S; Imitola, Jaime; Starossom, Sarah C et al. (2015) Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis. Glycobiology 25:1392-409
Abdi, Reza; Moore, Robert; Sakai, Shinobu et al. (2015) HCELL Expression on Murine MSC Licenses Pancreatotropism and Confers Durable Reversal of Autoimmune Diabetes in NOD Mice. Stem Cells 33:1523-31
Sackstein, Robert; Fuhlbrigge, Robert (2015) Western blot analysis of adhesive interactions under fluid shear conditions: the blot rolling assay. Methods Mol Biol 1312:399-410
Silvescu, Cristina I; Sackstein, Robert (2014) G-CSF induces membrane expression of a myeloperoxidase glycovariant that operates as an E-selectin ligand on human myeloid cells. Proc Natl Acad Sci U S A 111:10696-701
Peter, Yakov; Sen, Namita; Levantini, Elena et al. (2013) CD45/CD11b positive subsets of adult lung anchorage-independent cells harness epithelial stem cells in culture. J Tissue Eng Regen Med 7:572-83
Sackstein, Robert (2012) Engineering cellular trafficking via glycosyltransferase-programmed stereosubstitution. Ann N Y Acad Sci 1253:193-200
Sackstein, Robert (2012) Glycoengineering of HCELL, the human bone marrow homing receptor: sweetly programming cell migration. Ann Biomed Eng 40:766-76
Thankamony, Sai P; Sackstein, Robert (2011) Enforced hematopoietic cell E- and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells. Proc Natl Acad Sci U S A 108:2258-63
Merzaban, Jasmeen S; Burdick, Monica M; Gadhoum, S Zeineb et al. (2011) Analysis of glycoprotein E-selectin ligands on human and mouse marrow cells enriched for hematopoietic stem/progenitor cells. Blood 118:1774-83

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