title: Intermittent hypoxia mobilizes bone marrow-derived very small embryonic-like stem cells and activates developmental transcriptional programs in mice.
abstract: BACKGROUND
  obstructive sleep apnea is a prevalent disorder associated with cognitive dysfunction and cardiovascular and metabolic morbidity and is characterized by recurrent episodes of hypoxia during sleep. Bone marrow-derived very small embryonic-like (VSEL) pluripotent stem cells represent a recruitable pool that may play an important role in organ repair after injury. We hypothesized that exposure to intermittent hypoxia (IH) can mobilize VSELs from the bone marrow (BM) to peripheral blood (PB) in mice and can activate distinct transcriptional programs.
  
  
  METHODS
  adult mice were exposed to IH or normoxia for 48 hours. VSELs were sorted from BM and PB using flow cytometry. Plasma levels of stem cell chemokines, stromal cell derived factor-1 (SDF-1), hepatocyte growth factor (HGF), and leukemia inhibitory factor (LIF) were measured. Transcriptional profiling of VSELs was performed, and differentially expressed genes were mapped to enriched functional categories and genetic networks.
  
  
  RESULTS
  exposure to IH elicited migration of VSELs from BM to PB and elevations in plasma levels of chemokines. More than 1100 unique genes were differentially expressed in VSELs in response to IH. Gene Ontology and network analysis revealed the activation of organ-specific developmental programs among these genes.
  
  
  CONCLUSIONS
  exposure to IH mobilizes VSELs from the BM to PB and activates distinct transcriptional programs in VSELs that are enriched in developmental pathways, including central nervous system development and angiogenesis. Thus, VSELs may serve as a reserve mobile pool of pluripotent stem cells that can be recruited into PB and may play an important role in promoting end-organ repair during IH.
authors.affiliation: Center for Lung Biology and UW Medicine Sleep Instiute, Department of Medicine, University of Washington, WA, USA.
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.forename: Ehab A
authors.initials: EA
authors.lastname: Dayyat
authors.forename: Abdelnaby
authors.initials: A
authors.lastname: Khalyfa
authors.forename: Jinkwan
authors.initials: J
authors.lastname: Kim
authors.forename: Heather B
authors.initials: HB
authors.lastname: Clair
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kucia
authors.forename: David
authors.initials: D
authors.lastname: Gozal
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001854:Bone Marrow Cells / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000097:blood; D018925:Chemokines / Q000097:blood; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000097:blood; D000860:Hypoxia / Q000097:blood* / Q000503:physiopathology; D053605:Leukemia Inhibitory Factor / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis / Q000379:methods; D025341:Principal Component Analysis
chemical_list: D015415:Biomarkers; D054377:Chemokine CXCL12; D018925:Chemokines; D053605:Leukemia Inhibitory Factor; D017228:Hepatocyte Growth Factor