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Quantitative Stability of Hematopoietic Stem and Progenitor Cell Clonal Output in Transplanted Rhesus Macaques

Samson J. Koelle, Diego A. Espinoza, Chuanfeng Wu, Jason Xu, Rong Lu, Brian Li, Robert E. Donahue and Cynthia E. Dunbar

Key points

  • Output from individual rhesus macaque hematopoietic stem and progenitor cells is stable for years, with little evidence of clonal succession

  • Individual clones may display stable myeloid or lymphoid bias for many years

Abstract

Autologous transplantation of hematopoietic stem and progenitor cells lentivirally labeled with unique oligonucleotide barcodes flanked by sequencing primer targets enables quantitative assessment of the self-renewal and differentiation patterns of these cells in a myeloablative rhesus macaque model. Compared with other approaches to clonal tracking, this approach is highly quantitative and reproducible. We documented very stable multipotent long-term hematopoietic clonal output of monocytes, granulocytes, B cells and T cells from a polyclonal pool of hematopoietic stem and progenitor cells in four macaques followed for up to 49 months post-transplantation. A broad range of clonal behaviors characterized by contribution level and biases towards certain cell types were extremely stable over time. Correlations between granulocyte and monocyte clonalities were greatest, followed by correlations between these cell types and B cells. We also detected quantitative expansion of T cell biased clones consistent with an adaptive immune response. In contrast to recent data from a non-quantitative murine model, there was little evidence for clonal succession after initial hematopoietic reconstitution. These findings have important implications for human hematopoiesis, given the similarities between macaque and human physiology.

  • Submitted July 22, 2016.
  • Accepted January 4, 2017.