title: Notch-induced hIL-6 production facilitates the maintenance of self-renewal of hCD34+ cord blood cells through the activation of Jak-PI3K-STAT3 pathway.
abstract: Ex vivo expansion of CD34(+) stem cells in contact culture between hCD34(+)CD38(-)Lin(-) cord blood stem cells and human delta-like-expressing AFT024 feeder cells revealed increased amounts of stemness-related proteins such as HoxB4, GATA2, Bmi-1, and p21 and anti-apoptotic proteins such as Bcl-2, Bcl-xL, Mcl-1, and phospho-Bad, when compared with control or noncontact culture. Production of human IL-6 (hIL-6) was markedly elevated in the culture, but was profoundly inhibited by treatment with γ-secretase inhibitor. In addition, Notch-induced activation of STAT3 was directly involved in gene expression of hIL-6 and soluble hIL-6Rα, indicating the close linkage between Notch signaling and hIL-6 production. Furthermore, depletion of soluble hIL-6 (with hIL-6-specific antibodies) and inhibition of IL-6-mediated signals (with a Jak1 inhibitor and wortmannin) severely affected the maintenance of self-renewal of hCD34(+) cord blood cells. It was also observed that the ex vivo expanded CD34(+) cord blood cells were induced to reconstitute human immune cells in nonobese diabetic mice with severe combined immunodeficiency when compared with freshly isolated CD34(+) cord blood cells. Together, these results strongly demonstrate that Notch signaling in the "cell-to-cell contact" between hCD34(+) cord blood and delta-like-expressing AFT024 feeder cells facilitates maintenance of self-renewal of hCD34(+) cord blood cells through direct regulation of hIL-6 production.
authors: Department of Molecular Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors: Bongkum
authors: B
authors: Choi
authors: Eunyoung
authors: E
authors: Chun
authors: So Yong
authors: SY
authors: Kim
authors: Miyoung
authors: M
authors: Kim
authors: Ki-Young
authors: KY
authors: Lee
authors: Sung Joo
authors: SJ
authors: Kim
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D001773:Blood Cells / Q000276:immunology*; D049109:Cell Proliferation; D005312:Fetal Blood / Q000166:cytology*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051880:Receptors, Notch / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000502:physiology
chemical_list: D018952:Antigens, CD34; D015850:Interleukin-6; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D053613:Janus Kinase 1