Selective Enhancement of Donor Hematopoietic Cell Engraftment by the CXCR4 Antagonist AMD3100 in a Mouse Transplantation Model

The interaction between stromal cell-derived factor-1 (SDF-1) with CXCR4 chemokine receptors plays an important role in hematopoiesis following hematopoietic stem cell transplantation. We examined the efficacy of post transplant administration of a specific CXCR4 antagonist (AMD3100) in improving animal survival and in enhancing donor hematopoietic cell engraftment using a congeneic mouse transplantation model. AMD3100 was administered subcutaneously at 5 mg/kg body weight 3 times a week beginning at day +2 post-transplant. Post-transplant administration of AMD3100 significantly improves animal survival. AMD3100 reduces pro-inflammatory cytokine/chemokine production. Furthermore, post transplant administration of AMD3100 selectively enhances donor cell engraftment and promotes recovery of all donor cell lineages (myeloid cells, T and B lymphocytes, erythrocytes and platelets). This enhancement results from a combined effect of increased marrow niche availability and greater cell division induced by AMD3100. Our studies shed new lights into the biological roles of SDF-1/CXCR4 interaction in hematopoietic stem cell engraftment following transplantation and in transplant-related mortality. Our results indicate that AMD3100 provides a novel approach for enhancing hematological recovery following transplantation, and will likely benefit patients undergoing transplantation

Osmoregulatory Physiology and its Evolution in the Threespine Stickleback (Gasterosteus aculeatus)

Maintaining ion balance in environments of changing salinity is one of the greatest physiological challenges facing aquatic organisms and by comparing populations inhabiting different salinity regimes, we can learn how physiological plasticity evolves in response to local osmotic stress. I characterized the evolution of osmoregulatory responses in representative marine, anadromous, and freshwater (FW) populations of Threespine Stickleback (Gasterosteus aculeatus) by comparing survival and physiological measures in F1-generation fish following salinity challenge. Juveniles from a population landlocked for ~10,000 years displayed ontogenetically-delayed seawater (SW) tolerance, a lower maximum salinity threshold, and did not upregulate the Na+/K+-ATPase (NKA) ion transporter as much as marine counterparts (Chapter 1). Stickleback also responded to salinity stress by remodeling their gill epithelium: I observed a higher density of ionoregulatory cells when juveniles were subjected to both low and high salinities, and the latter treatment induced strong upregulation of ion secretory cells (Chapter 2). Finally, I examined the speed at which osmoregulatory plasticity evolves by comparing halotolerance between an anadromous population and descendants that had been FW-restricted for only two generations (Chapter 3). The lake-introduced group had improved survival in FW, but also retained SW tolerance and had similar increases in gill NKA activity, gill Na+/K+/2Cl- cotransporter abundance, and organic osmolytes in SW. Overall, the differentiated responses to salinity I observed among stickleback populations indicate that osmoregulation has evolved in a manner consistent with local adaptation and following FW invasions, positive selection on FW tolerance acts more rapidly than relaxed selection on SW tolerance