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, Ontogeny, OSKM, Sendai virus
dx.doi.org/10.1002/stem.2303, hdl.handle.net/1765/91193
Stem Cells: the international journal of cell differentiation and proliferation
Department of Pediatrics

Muñoz-López, Á, van Roon, E.H.J, Romero-Moya, D, López-Millan, B, Stam, R.W, Colomer, D, … Menéndez, P. (2016). Cellular ontogeny and hierarchy influence the reprogramming efficiency of human B cells into induced pluripotent stem cells. Stem Cells: the international journal of cell differentiation and proliferation, 34(3), 581–587. doi:10.1002/stem.2303