Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans

S Scala, L Basso-Ricci, F Dionisio, D Pellin, S Giannelli, FA Salerio, L Leonardelli, MP Cicalese, F Ferrua, A Aiuti, L Biasco

Research output: Contribution to journalArticle

Abstract

Hematopoietic stem and progenitor cells (HSPC) are endowed with the role of generating and maintaining lifelong the extremely diverse pool of blood cells1. Clinically, transplantation of human HSPC from an allogeneic healthy donor or infusion of autologous gene-corrected HSPC can effectively replenish defective blood cell production caused by congenital or acquired disorders2–9. However, due to methodological and ethical constraints that have limited the study of human HSPC primarily to in vitro assays10or xenotransplantation models11,12, the in vivo activity of HSPC has to date remained relatively unexplored in humans13–16. Here we report a comprehensive study of the frequencies, dynamics and output of seven HSPC subtypes in humans that was performed by tracking 148,093 individual clones in six patients treated with lentiviral gene therapy using autologous HSPC transplantation and followed for up to 5 years. We discovered that primitive multipotent progenitor and hematopoietic stem cell (HSC) populations have distinct roles during the initial reconstitution after transplant, compared with subsequent steady-state phases. Furthermore, we showed that a fraction of in vitro–activated HSC are resilient and undergo a defined delayed activation period upon transplant. Finally, our data support the concept that early lymphoid-biased progenitors might be capable of long-term survival, such that they can be maintained independently of their continuous production from HSC. Overall, this study provides comprehensive data on HSPC dynamics after autologous transplantation and gene therapy in humans. © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
Original languageEnglish
Pages (from-to)1683-1690
Number of pages8
JournalNature Medicine
Volume24
Issue number11
DOIs
Publication statusPublished - 2018

Fingerprint

Autologous Transplantation
Hematopoietic Stem Cells
Stem cells
Gene therapy
Transplants
Blood
Genes
Chemical activation
Cells
Genetic Therapy
Multipotent Stem Cells
Heterologous Transplantation
Hematopoietic Stem Cell Transplantation
Licensure

Cite this

Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans. / Scala, S; Basso-Ricci, L; Dionisio, F; Pellin, D; Giannelli, S; Salerio, FA; Leonardelli, L; Cicalese, MP; Ferrua, F; Aiuti, A; Biasco, L.

In: Nature Medicine, Vol. 24, No. 11, 2018, p. 1683-1690.

Research output: Contribution to journalArticle

@article{02d5453f15b24f91aaba1733dcaa07b0,
title = "Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans",
abstract = "Hematopoietic stem and progenitor cells (HSPC) are endowed with the role of generating and maintaining lifelong the extremely diverse pool of blood cells1. Clinically, transplantation of human HSPC from an allogeneic healthy donor or infusion of autologous gene-corrected HSPC can effectively replenish defective blood cell production caused by congenital or acquired disorders2–9. However, due to methodological and ethical constraints that have limited the study of human HSPC primarily to in vitro assays10or xenotransplantation models11,12, the in vivo activity of HSPC has to date remained relatively unexplored in humans13–16. Here we report a comprehensive study of the frequencies, dynamics and output of seven HSPC subtypes in humans that was performed by tracking 148,093 individual clones in six patients treated with lentiviral gene therapy using autologous HSPC transplantation and followed for up to 5 years. We discovered that primitive multipotent progenitor and hematopoietic stem cell (HSC) populations have distinct roles during the initial reconstitution after transplant, compared with subsequent steady-state phases. Furthermore, we showed that a fraction of in vitro–activated HSC are resilient and undergo a defined delayed activation period upon transplant. Finally, our data support the concept that early lymphoid-biased progenitors might be capable of long-term survival, such that they can be maintained independently of their continuous production from HSC. Overall, this study provides comprehensive data on HSPC dynamics after autologous transplantation and gene therapy in humans. {\circledC} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.",
author = "S Scala and L Basso-Ricci and F Dionisio and D Pellin and S Giannelli and FA Salerio and L Leonardelli and MP Cicalese and F Ferrua and A Aiuti and L Biasco",
year = "2018",
doi = "10.1038/s41591-018-0195-3",
language = "English",
volume = "24",
pages = "1683--1690",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans

AU - Scala, S

AU - Basso-Ricci, L

AU - Dionisio, F

AU - Pellin, D

AU - Giannelli, S

AU - Salerio, FA

AU - Leonardelli, L

AU - Cicalese, MP

AU - Ferrua, F

AU - Aiuti, A

AU - Biasco, L

PY - 2018

Y1 - 2018

N2 - Hematopoietic stem and progenitor cells (HSPC) are endowed with the role of generating and maintaining lifelong the extremely diverse pool of blood cells1. Clinically, transplantation of human HSPC from an allogeneic healthy donor or infusion of autologous gene-corrected HSPC can effectively replenish defective blood cell production caused by congenital or acquired disorders2–9. However, due to methodological and ethical constraints that have limited the study of human HSPC primarily to in vitro assays10or xenotransplantation models11,12, the in vivo activity of HSPC has to date remained relatively unexplored in humans13–16. Here we report a comprehensive study of the frequencies, dynamics and output of seven HSPC subtypes in humans that was performed by tracking 148,093 individual clones in six patients treated with lentiviral gene therapy using autologous HSPC transplantation and followed for up to 5 years. We discovered that primitive multipotent progenitor and hematopoietic stem cell (HSC) populations have distinct roles during the initial reconstitution after transplant, compared with subsequent steady-state phases. Furthermore, we showed that a fraction of in vitro–activated HSC are resilient and undergo a defined delayed activation period upon transplant. Finally, our data support the concept that early lymphoid-biased progenitors might be capable of long-term survival, such that they can be maintained independently of their continuous production from HSC. Overall, this study provides comprehensive data on HSPC dynamics after autologous transplantation and gene therapy in humans. © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.

AB - Hematopoietic stem and progenitor cells (HSPC) are endowed with the role of generating and maintaining lifelong the extremely diverse pool of blood cells1. Clinically, transplantation of human HSPC from an allogeneic healthy donor or infusion of autologous gene-corrected HSPC can effectively replenish defective blood cell production caused by congenital or acquired disorders2–9. However, due to methodological and ethical constraints that have limited the study of human HSPC primarily to in vitro assays10or xenotransplantation models11,12, the in vivo activity of HSPC has to date remained relatively unexplored in humans13–16. Here we report a comprehensive study of the frequencies, dynamics and output of seven HSPC subtypes in humans that was performed by tracking 148,093 individual clones in six patients treated with lentiviral gene therapy using autologous HSPC transplantation and followed for up to 5 years. We discovered that primitive multipotent progenitor and hematopoietic stem cell (HSC) populations have distinct roles during the initial reconstitution after transplant, compared with subsequent steady-state phases. Furthermore, we showed that a fraction of in vitro–activated HSC are resilient and undergo a defined delayed activation period upon transplant. Finally, our data support the concept that early lymphoid-biased progenitors might be capable of long-term survival, such that they can be maintained independently of their continuous production from HSC. Overall, this study provides comprehensive data on HSPC dynamics after autologous transplantation and gene therapy in humans. © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.

U2 - 10.1038/s41591-018-0195-3

DO - 10.1038/s41591-018-0195-3

M3 - Article

VL - 24

SP - 1683

EP - 1690

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 11

ER -