Cellular Ontogeny and Hierarchy Influence the Reprogramming Efficiency of Human B Cells into Induced Pluripotent Stem Cells
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. Stem Cells 2016;34:581 587
Stem cells