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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.

Author information

1
Josep Carreras Leukemia Research Institute (IJC) and School of Medicine, Department of Biomedicine, University of Barcelona, Barcelona, Spain.
2
Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
3
Hematopathology Unit, Department of Anatomic Pathology, Hospital Clinic, IDIBAPS, Barcelona, Spain.
4
Research Center for Stem Cell Engineering and National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraka, Japan.
5
Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

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.

KEYWORDS:

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

PMID:
26850912
DOI:
10.1002/stem.2303
[Indexed for MEDLINE]
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