title: Cellular Ontogeny and Hierarchy Influence the Reprogramming Efficiency of Human B Cells into Induced Pluripotent Stem Cells.
abstract: Although B cells have been shown to be refractory to reprogramming into pluripotency, induced pluripotent stem cells (iPSCs) have been very recently generated, at very low efficiency, from human cord blood (CB)- and peripheral blood (PB)-derived CD19+CD20 + B cells using nonintegrative tetracistronic OSKM-expressing Sendai Virus (SeV). Here, we addressed whether cell ontogeny and hierarchy influence the reprogramming efficiency of the B-cell compartment. We demonstrate that human fetal liver (FL)-derived CD19 + B cells are 110-fold easier to reprogram into iPSCs than those from CB/PB. Similarly, FL-derived CD34+CD19 + B progenitors are reprogrammed much easier than mature B cells (0.46% vs. 0.11%). All FL B-cell iPSCs carry complete VDJH rearrangements while 55% and 45% of the FL B-progenitor iPSCs carry incomplete and complete VDJH rearrangements, respectively, reflecting the reprogramming of developmentally different B progenitors (pro-B vs. pre-B) within a continuous differentiation process. Finally, our data suggest that successful B-cell reprogramming relies on active cell proliferation, and it is MYC-dependent as identical nonintegrative polycistronic SeV lacking MYC (OSKL or OSKLN) fail to reprogram B cells. The ability to efficiently reprogram human fetal primary B cells and B precursors offers an unprecedented opportunity for studying developmental B-lymphopoiesis and modeling B-cell malignances.
authors: Josep Carreras Leukemia Research Institute (IJC) and School of Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain.
authors: Álvaro
authors: Á
authors: Muñoz-López
authors: Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Eddy H J
authors: EH
authors: van Roon
authors: Josep Carreras Leukemia Research Institute (IJC) and School of Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain.
authors: Damià
authors: D
authors: Romero-Moya
authors: Josep Carreras Leukemia Research Institute (IJC) and School of Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain.
authors: Belén
authors: B
authors: López-Millan
authors: Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Ronald W
authors: RW
authors: Stam
authors: Hematopathology Unit, Department of Anatomic Pathology, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors: Dolors
authors: D
authors: Colomer
authors: Research Center for Stem Cell Engineering and National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraka, Japan.
authors: Mahito
authors: M
authors: Nakanishi
authors: Josep Carreras Leukemia Research Institute (IJC) and School of Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain.
authors: Clara
authors: C
authors: Bueno
authors: Josep Carreras Leukemia Research Institute (IJC) and School of Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain.|Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors: Pablo
authors: P
authors: Menendez
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics*; D005312:Fetal Blood / Q000166:cytology; D005822:Genetic Vectors; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics
chemical_list: D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016271:Proto-Oncogene Proteins c-myc; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D011495:Histone-Lysine N-Methyltransferase
keywords: Fetal liver; Hierarchy; Human B cells; Human B-cell progenitors; Ig gene rearrangements; Induced pluripotent stem cells; OSKM; Ontogeny; Sendai virus