University of Virginia Patent Foundation

Mary J Laughlin

Kevin R Lynch

Edward A Botchwey, Iii

Anthony Awojoodu

Mariusz Z Ratajczak

Anusuya Das

Claudio Brunstein

The present application discloses strategies to recruit and mobilize stem cells using S1P receptor selective agonists and antagonists as wells as regulators of chemokine receptors. In an in vivo ischemic model, S1P/S1Pactivation with FTY720 impeded inflammatory cell infiltration and recruited endothelial progenitor cells (EPCs) with the potential to increase microvascular remodeling. S1Pexpression on marrow-derived cells was essential for this remodeling. Concurrent systemic S1Pand CXCR4 antagonism mobilized hematopoietic stem cells (HSCs) with the ability to engraft and repopulate blood cells. Pre-treatment of donor HSCs with FTY720 increased homing toward SDF-1 and improved engraftment in marrow. FTY720-coated bone allografts coupled with systemic administration of VPC01091 enhanced bone allograft integration and new bone formation in bone defects. MSCs pre-treated with FTY720 exhibited increased migration toward SDF-1, a CXCR4+ ligand. The results show that S1P is a very powerful role player in pharmacological marrow-derived stem cell mobilization and recruitment.

Compositions and methods for tissue engineering and cell based therapies

The present invention provides for enhancing engraftment by co-infusing at least two partially HLA matched umbilical cord blood ('UCB') units. The invention further provides for positive C3a mediated priming on responsiveness to doses of SDF-1 and C3a induced incorporation of CXCR4 in membranes in HSC and progenitors. The invention further provides for enhancing the homing of UCB HSC and progenitors via the SDF-1/CXCR4 pathway and that C3a and LL-37 are useful for this method. It is also disclosed herein that fragments of C3a (e.g., des-Arg) are effective in the methods of the invention, including enhancing homing of HSPCs to BM. The invention further encompasses the disclosure herein of NFAT1 regulation post-transcriptionally by both mir-184 and IFN-&#x3b3;. The present invention further provides for measuring and using differences between UCB and adult CD4+/45RA+ T-cells as a means of defining strategies to enhance optimal allogeneic stem cell transplantation outcomes. The present invention further provides methods for maintaining IL-2 production in the absence of NFAT1 normal protein levels.

Compositions and methods for CXCR4 signaling and umbilical cord blood stem cell engraftment

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Crozet, VA, United States of America

Mary J Laughlin