Dynamics of HSPC Repopulation in Nonhuman Primates Revealed by a Decade-Long Clonal-Tracking Study

Abstract

SUMMARY In mice, clonal tracking of hematopoietic stem cells has revealed variations in repopulation characteristics. However, it is unclear whether similar properties apply in primates. Here, we examined this issue through tracking of thousands of hematopoietic stem and progenitor cells (HSPCs) in rhesus macaques for up to 12 years. Approximately half of the clones analyzed contributed to long-term repopulation (over 3–10 years) and likely represent self-renewing hematopoietic stem cells (HSCs), while the remainder contributed primarily for the first year. The long-lived clones could be further subdivided into functional groups contributing primarily to myeloid, lymphoid or both lineages. Over time, the 4–10% of clones with robust dual lineage contribution predominated in repopulation capacity. HSPCs expressing a CCR5 shRNA transgene behaved similarly to controls. Our study therefore documents HSPC behavior in a clinically-relevant model over a long time frame, and provides a substantial system-level dataset that is a reference point for future work.

In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors

“…In non-human primate and human studies with ex vivo lentivirus vector-transduced HSCs, it was estimated that one in 1 million transplanted HSCs were capable of long-term repopulation. 32,33 In the human trials, this would correspond to 200 to 300 gene-corrected, long-term engrafting cells per 1.5 3 10 12 total MNCs in the human BM. 4 The fact that our approach allows for the transduction of primitive HSPCs and that the percentage of these cells increases over time ( Figure 3B), suggests that transduced HSPCs self-renew and give rise to GFP 1 progeny cells that slowly overtake the BM.…”

Clonal Tracking of Rhesus Macaque Hematopoiesis Highlights a Distinct Lineage Origin for Natural Killer Cells

“…However, hematopoietic tracking for much longer time periods is required to determine the frequency and clonal output of true long-term repopulating cells, and to distinguish models of HSC clonal exhaustion/succession versus clonal stability. A related study from our primate program, published in this issue, has utilized very long-term lentiviral VIS retrieval to provide answers to some of these questions (Kim et al, 2014). Longer follow-up combined with barcoding will allow additional highly quantitative analysis of whether lineage-skewed classes of HSCs exist in non-human primates, analogous to recent findings in murine models regarding lymphoid versus myeloid biased HSC and our companion long-term primate study (Copley et al, 2012)(Kim et al, 2014).…”

Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand?

“…[65][66][67][68][69] Similar work in humans can now be performed by efficient RIS analysis, as illustrated in a study highlighting the long-term survival of T memory stem cells. 70 The long-term follow-up of the dynamics of naive and memory T cell populations in the SCIDX1 trials will also enable us to better understand human thymopoiesis and immune responses.…”