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Cell Stem Cell. 2016 Jul 7;19(1):107-19. doi: 10.1016/j.stem.2016.04.016. Epub 2016 May 26.

In Vivo Tracking of Human Hematopoiesis Reveals Patterns of Clonal Dynamics during Early and Steady-State Reconstitution Phases.

Author information

1
San Raffaele Telethon Institute for Gene Therapy (TIGET), 20132 Milan, Italy. Electronic address: biasco.luca@hsr.it.
2
CUSSB, Vita-Salute University, 20132 Milan, Italy.
3
San Raffaele Telethon Institute for Gene Therapy (TIGET), 20132 Milan, Italy.
4
San Raffaele Telethon Institute for Gene Therapy (TIGET), 20132 Milan, Italy; Pediatric Immunohematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, 20132 Milan, Italy.
5
Target Sciences, GlaxoSmithKline R&D, Stevenage, Herts SG1 2NY, UK.
6
National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
7
San Raffaele Telethon Institute for Gene Therapy (TIGET), 20132 Milan, Italy; Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA.
8
Pediatric Immunohematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, 20132 Milan, Italy.
9
Department of Economy, University Roma Tre, 00154 Rome, Italy.
10
Johann Bernoulli Institute, University of Groningen, 9700 AB Groningen, the Netherlands.
11
CUSSB, Vita-Salute University, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy.
12
San Raffaele Telethon Institute for Gene Therapy (TIGET), 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy.
13
San Raffaele Telethon Institute for Gene Therapy (TIGET), 20132 Milan, Italy; Pediatric Immunohematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy. Electronic address: aiuti.alessandro@hsr.it.

Abstract

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.

PMID:
27237736
PMCID:
PMC4942697
DOI:
10.1016/j.stem.2016.04.016
[Indexed for MEDLINE]
Free PMC Article

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