title: Distinct stromal cell factor combinations can separately control hematopoietic stem cell survival, proliferation, and self-renewal.
abstract: Hematopoietic stem cells (HSCs) are identified by their ability to sustain prolonged blood cell production in vivo, although recent evidence suggests that durable self-renewal (DSR) is shared by HSC subtypes with distinct self-perpetuating differentiation programs. Net expansions of DSR-HSCs occur in vivo, but molecularly defined conditions that support similar responses in vitro are lacking. We hypothesized that this might require a combination of factors that differentially promote HSC viability, proliferation, and self-renewal. We now demonstrate that HSC survival and maintenance of DSR potential are variably supported by different Steel factor (SF)-containing cocktails with similar HSC-mitogenic activities. In addition, stromal cells produce other factors, including nerve growth factor and collagen 1, that can antagonize the apoptosis of initially quiescent adult HSCs and, in combination with SF and interleukin-11, produce >15-fold net expansions of DSR-HSCs ex vivo within 7 days. These findings point to the molecular basis of HSC control and expansion.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Landesklinikum Wr. Neustadt, Internal Medicine 1, Wr. Neustadt 2700, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wohrer
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: David J H F
authors.initials: DJ
authors.lastname: Knapp
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Copley
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Benz
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Kent
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Keegan
authors.initials: K
authors.lastname: Rowe
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Sonja
authors.initials: S
authors.lastname: Babovic
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Heidi
authors.initials: H
authors.lastname: Mader
authors.affiliation: 3(rd) Department of Internal Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich 81675, Germany.
authors.forename: Robert A J
authors.initials: RA
authors.lastname: Oostendorp
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada. Electronic address: ceaves@bccrc.ca.
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism*