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Publication Number
US-8846393-B2
Publication Date
2014-09-30
Expiration Date
Abstract
A method of enhancing cell engraftment potential is provided. The method comprising ex-vivo or in-vitro subjecting a population of cells to an amount of nicotinamide for a period of time sufficient to effect the population of cells, thereby enhancing cell engraftment potential.
Core Innovation
The invention relates to enhancing cell homing and engraftment potential by ex-vivo or in vitro culturing an isolated CD34+ hematopoietic stem cell population in the presence of nicotinamide. The culturing is performed for a period of time that is insufficient for proliferation of the isolated CD34+ hematopoietic stem cells, and the culturing results in down-regulation of CD26 expression compared to isolated CD34+ hematopoietic stem cells cultured in the absence of nicotinamide.
The approach uses nicotinamide rather than prior CD26 inhibitor approaches characterized as catalytic inhibition. The document contrasts these prior approaches with down-regulation of CD26 surface expression while avoiding promotion of stem cell proliferation or expansion. The described outcome is improved adhesion and integrin and chemokine-receptor function, including increased responsiveness to CXCL12 (SDF-1α) and improved binding and retention involving VLA-4 and VCAM-1.
The document reports supporting findings showing CD26 reduction after exposure to nicotinamide and enhanced functional readouts associated with homing and engraftment. It also discusses use of enhanced cell populations for transplantation across hematopoietic contexts and other tissues, including experiments involving NOD/SCID and SCID repopulating cells. Reported results include increased bone marrow homing, increased CXCL12-induced migration, improved shear-flow VCAM-1 retention, and increased SCID repopulating cell frequency and engraftment at suboptimal doses.
Claims Coverage
The independent claim identifies a method to enhance cell homing and engraftment potential using ex-vivo or in vitro culturing of isolated CD34+ hematopoietic stem cells with nicotinamide under conditions that avoid proliferation and produce CD26 down-regulation. No other independent claims are provided in the supplied claim set; the remaining claims appear as dependent refinements of this core method.
Enhancing cell homing and engraftment via nicotinamide-conditioned CD34+ cells
Ex-vivo or in vitro culturing a population of isolated CD34+ hematopoietic stem cells in the presence of nicotinamide for a period of time insufficient for proliferation, wherein said culturing results in down-regulation of CD26 expression compared to isolated CD34+ hematopoietic stem cells cultured in the absence of nicotinamide.
Nicotinamide concentration and culture duration within the claimed range
The nicotinamide conditioned culture is characterized by specific constraints, including culturing with 5 mM nicotinamide for 20 hours.
Nicotinamide component selected from nicotinamide and nicotinamide-related compounds
The nicotinamide used is selected from nicotinamide, nicotinamide analogs, nicotinamide metabolites, nicotinamide analog metabolites, and derivatives thereof.
Permissible sources of the CD34+ hematopoietic stem cell population
Obtaining the CD34+ hematopoietic stem cell population from umbilical cord blood cells, mobilized peripheral blood cells, or bone marrow cells.
CD34-enriched selection in relation to ex-vivo culturing
Selecting a CD34-enriched population of cells containing hematopoietic stem cells either before, during, or after ex-vivo culturing.
CD34/CD38 selection markers
Selecting the CD34-enriched population using CD34/CD38.
Across the provided independent claim and its dependent refinements, the inventive coverage centers on ex-vivo or in vitro culturing CD34+ hematopoietic stem cells with nicotinamide for a non-proliferative period that down-regulates CD26, with refinements specifying nicotinamide-related compounds, permissible cell sources, and CD34-(optionally CD34/CD38)-based selection timing and markers.
Stated Advantages
Enhances cell homing and engraftment potential.
Down-regulates CD26 expression compared to culturing without nicotinamide.
Improves adhesion and integrin and chemokine-receptor function, including CXCL12 responsiveness and VLA-4/VCAM-1 binding and retention.
Documented Applications
Use of enhanced cell populations for transplantation, including hematopoietic transplantation contexts.
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