Adult blood vessels restore host hematopoiesis following lethal irradiation.

OBJECTIVE: Accumulating evidence indicates a common stem cell may be responsible for both vasculogenesis and blood cell production during early embryologic development, yet little is known about the fate of these cells during ontogeny. We sought to determine whether hematopoietic potential is associated with normal blood vessels in the adult. MATERIALS AND METHODS: Segments of adult thoracic aorta or inferior vena cava were transplanted under the kidney capsule of lethally irradiated recipients (1100 cGy). Radioprotection, colony-forming units (CFUs), and the extent of donor-derived hematopoietic constitution were evaluated using both Ly5 congenic and ROSA26 donor mice. RESULTS: As little as 10 mg of transplanted vascular tissue radioprotected 80% of recipients, gave rise to similar numbers of CFUs as 10(5) bone marrow cells and prevented the development of severe anemia. Bromodeoxyuridine labeling studies revealed cell proliferation within the intima of donor vascular tissue within 48 hours of transplantation. ROSA26 donor-derived vascular cells migrated to the recipient spleen; however, CFUs were of host origin, a finding confirmed using sex-mismatched transplants. Although donor-derived cells were readily detected in the peripheral blood 2 to 3 weeks after transplant, they rapidly declined in frequency to approximately 1.0% by 4 weeks and persisted at these levels for more than 1 year. Bone marrow from rescued primary recipients provided radioprotection after transplantation into secondary recipients; however, only CD3(+) donor-derived cells were detected. CONCLUSION: These findings demonstrate the presence of a population of cells within normal adult vascular tissue that has the capacity to protect host hematopoietic stem cells from radiation-induced death.

Inhibition of Mer and Axl receptor tyrosine kinases in astrocytoma cells leads to increased apoptosis and improved chemosensitivity.

Astrocytomas account for the majority of malignant brain tumors diagnosed in both adult and pediatric patients. The therapies available to treat these neoplasms are limited, and the prognosis associated with high-grade lesions is extremely poor. Mer (MerTK) and Axl receptor tyrosine kinases (RTK) are expressed at abnormally high levels in a variety of malignancies, and these receptors are known to activate strong antiapoptotic signaling pathways that promote oncogenesis. In this study, we found that Mer and Axl mRNA transcript and protein expression were elevated in astrocytic patient samples and cell lines. shRNA-mediated knockdown of Mer and Axl RTK expression led to an increase in apoptosis in astrocytoma cells. Apoptotic signaling pathways including Akt and extracellular signal-regulated kinase 1/2, which have been shown to be activated in resistant astrocytomas, were downregulated with Mer and Axl inhibition whereas poly(ADP-ribose) polymerase cleavage was increased. Furthermore, Mer and Axl shRNA knockdown led to a profound decrease of astrocytoma cell proliferation in soft agar and a significant increase in chemosensitivity in response to temozolomide, carboplatin, and vincristine treatment. Our results suggest Mer and Axl RTK inhibition as a novel method to improve apoptotic response and chemosensitivity in astrocytoma and provide support for these oncogenes as attractive biological targets for astrocytoma drug development.