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Stem Cells. 2016 Mar;34(3):581-7. doi: 10.1002/stem.2303. Epub 2016 Feb 25.

Cellular Ontogeny and Hierarchy Influence the Reprogramming Efficiency of Human B Cells into Induced Pluripotent Stem Cells.

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Josep Carreras Leukemia Research Institute (IJC) and School of Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain.
Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
Hematopathology Unit, Department of Anatomic Pathology, Hospital Clinic, IDIBAPS, Barcelona, Spain.
Research Center for Stem Cell Engineering and National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraka, Japan.
Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.


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.


Fetal liver; Hierarchy; Human B cells; Human B-cell progenitors; Ig gene rearrangements; Induced pluripotent stem cells; OSKM; Ontogeny; Sendai virus

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