SDF‐1/CXCL12 Enhances Survival and Chemotaxis of Murine Embryonic Stem Cells and Production of Primitive and Definitive Hematopoietic Progenitor Cells

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Abstract
Understanding embryonic stem cell (ESC) regulation is important for realizing how best to control their growth and differentiation ex vivo for potential therapeutic benefit. Stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor, CXCR4, have been implicated as important regulators of a number of fetal and adult cell functions, including survival/antiapoptosis and migration/homing of hematopoietic stem and progenitor cells. We hypothesized that the SDF-1/CXCL12-CXCR4 axis would also be important for regulation of murine ESC functions. ESCs secreted low levels of SDF-1/CXCL12 and expressed low levels of CXCR4; however, both increased with differentiation of ESCs. Endogenously produced/released SDF-1/CXCL12 enhanced survival/antiapoptosis of ESCs in the presence of leukemia inhibitory factor but absence of serum, and survival/antiapoptosis was further enhanced by exogenous administration of SDF-1/CXCL12. Furthermore, SDF-1/CXCL12 induced chemotaxis of ESCs, and chemotaxis could be enhanced by diprotin A inhibition of CD26/dipeptidylpeptidase IV. Endogenous and exogenous SDF-1/CXCL12 enhanced embryoid body production of primitive and definitive erythroid, granulocyte-macrophage, and multipotential progenitors. SDF-1/CXCL12 did not noticeably affect production of hemangioblasts. These results demonstrate functional activities of SDF-1/CXCL12 on survival, chemotaxis, and hematopoietic differentiation of murine ESCs that may be relevant for their ex vivo manipulation.