Luca Biasco 1 , ∗ , Danilo Pellin 2 , Serena Scala 1 , Francesca Dionisio 1 , Luca Basso-Ricci 1 , Lorena Leonardelli 1 , Samantha Scaramuzza 1 , Cristina Baricordi 1 , Francesca Ferrua 1 , 3 , Maria Pia Cicalese 1 , 3 , Stefania Giannelli 1 , Victor Neduva 4 , David J. Dow 4 , Manfred Schmidt 5 , Christof Von Kalle 5 , Maria Grazia Roncarolo 1 , 6 , Fabio Ciceri 3 , Paola Vicard 7 , Ernst Wit 8 , Clelia Di Serio 2 , 9 , Luigi Naldini 1 , 9 , Alessandro Aiuti 1 , 3 , 9 , ∗∗
07 July 2016
Hematopoietic stem/progenitor cells (HSPCs) are capable of supporting the lifelong production of blood cells exerting a wide spectrum of functions. Lentiviral vector HSPC gene therapy generates a human hematopoietic system stably marked at the clonal level by vector integration sites (ISs). Using IS analysis, we longitudinally tracked >89,000 clones from 15 distinct bone marrow and peripheral blood lineages purified up to 4 years after transplant in four Wiskott-Aldrich syndrome patients treated with HSPC gene therapy. We measured at the clonal level repopulating waves, populations' sizes and dynamics, activity of distinct HSPC subtypes, contribution of various progenitor classes during the early and late post-transplant phases, and hierarchical relationships among lineages. We discovered that in-vitro-manipulated HSPCs retain the ability to return to latency after transplant and can be physiologically reactivated, sustaining a stable hematopoietic output. This study constitutes in vivo comprehensive tracking in humans of hematopoietic clonal dynamics during the early and late post-transplant phases.
Hematopoietic reconstitution occurs in two distinct clonal waves
A few thousand HSPC clones stably sustain multilineage blood cell production
Steady-state hematopoiesis after transplant is maintained by both HSCs and MPPs
Natural killer clones have closer relationships to myeloid cells than to lymphoid cells
Biasco et al. report a clonal tracking study on the dynamics and nature of hematopoietic reconstitution in humans after transplant. Using integration sites as molecular tags, they measured, in gene therapy patients, repopulating waves, population size and dynamics, activity of progenitor subtypes during the early and late post-transplant phases, and hierarchical relationships among lineages.