title: Increased reprogramming capacity of mouse liver progenitor cells, compared with differentiated liver cells, requires the BAF complex.
abstract: OBJECTIVE
  Ectopic expression of certain transcription factors can reprogram somatic cells to a pluripotent state. Hematopoietic and muscle stem cells can be more efficiently reprogrammed than differentiated blood or muscle cells, yet similar findings have not been shown in other primary organ systems. Moreover, molecular characteristics of the cellular hierarchy of tissues that influence reprogramming capacities need to be delineated. We analyzed the effect of differentiation stage of freshly isolated, mouse liver cells on the reprogramming efficiency.
  
  
  METHODS
  Liver progenitor cell (LPC)-enriched cell fractions were isolated from adult (6-8 wk) and fetal (embryonic day 14.5) livers of mice and reprogrammed to become induced pluripotent stem (iPS) cells. Different transcription factors were expressed in liver cells, and markers of pluripotency were examined, along with the ability of iPS cells to differentiate, in vitro and in vivo, into different germ layers.
  
  
  RESULTS
  Fetal and adult LPCs had significantly greater reprogramming efficiency after transduction with 3 or 4 reprogramming factors. Transduction efficiency-corrected reprogramming rates of fetal LPCs were 275-fold higher, compared with unsorted fetal liver cells, when 3 reprogramming factors were transduced. The increased reprogramming efficiency of LPCs, compared with differentiated liver cells, occurred independently of proliferation rates, but was associated with endogenous expression of reprogramming factors (Klf4 and c-Myc) and BAF (Brg1/Brm associated factor)-complex members Baf155 and Brg1, which mediate epigenetic changes during reprogramming. Knockdown of BAF complex members negated the increased reprogramming efficiency of LPCs, compared with non-LPCs.
  
  
  CONCLUSIONS
  LPCs have intrinsic, cell proliferation-independent characteristics resulting in an increased reprogramming capacity compared to differentiated liver cells.
authors.affiliation: Institute of Molecular Medicine and Max-Planck-Research Department on Stem Cell Aging, Ulm University, Ulm, Germany. alexander.kleger@uni-ulm.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Kleger
authors.forename: Pallavi U
authors.initials: PU
authors.lastname: Mahaddalkar
authors.forename: Sarah-Fee
authors.initials: SF
authors.lastname: Katz
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Joo
authors.forename: Komal
authors.initials: K
authors.lastname: Loya
authors.forename: Qiong
authors.initials: Q
authors.lastname: Lin
authors.forename: Daniel
authors.initials: D
authors.lastname: Hartmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.forename: Johann M
authors.initials: JM
authors.lastname: Kraus
authors.forename: Tobias
authors.initials: T
authors.lastname: Cantz
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.forename: Holm
authors.initials: H
authors.lastname: Zaehres
authors.forename: Hans
authors.initials: H
authors.lastname: Schöler
authors.forename: Karl Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism*; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D015415:Biomarkers; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489428:Myc protein, mouse; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; C491090:Smarcc1 protein, mouse; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases