Dataset Information

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

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.

SUBMITTER: Biasco L

PROVIDER: S-EPMC4942697 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Biasco Luca L Pellin Danilo D Scala Serena S Dionisio Francesca F Basso-Ricci Luca L Leonardelli Lorena L Scaramuzza Samantha S Baricordi Cristina C Ferrua Francesca F Cicalese Maria Pia MP Giannelli Stefania S Neduva Victor V Dow David J DJ Schmidt Manfred M Von Kalle Christof C Roncarolo Maria Grazia MG Ciceri Fabio F Vicard Paola P Wit Ernst E Di Serio Clelia C Naldini Luigi L Aiuti Alessandro A

Cell stem cell 20160526 1

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 ...[more]

PMID: 27237736

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Project description:Oxygen levels in cancerous tissue can have a significant effect on treatment response: hypoxic tissue is both more radioresistant and more chemoresistant than well-oxygenated tissue. While recent advances in medical imaging have facilitated real-time observation of macroscopic oxygenation, the underlying physics limits the resolution to the millimetre domain, whereas oxygen tension varies over a micrometre scale. If the distribution of oxygen in the tumour micro-environment can be accurately estimated, then the effect of potential dose escalation to these hypoxic regions could be better modelled, allowing more realistic simulation of biologically adaptive treatments. Reaction-diffusion models are commonly used for modelling oxygen dynamics, with a variety of functional forms assumed for the dependence of oxygen consumption rate (OCR) on cellular status and local oxygen availability. In this work, we examine reaction-diffusion models of oxygen consumption in spherically and cylindrically symmetric geometries. We consider two different descriptions of oxygen consumption: one in which the rate of consumption is constant and one in which it varies with oxygen tension in a hyperbolic manner. In each case, we derive analytic approximations to the steady-state oxygen distribution, which are shown to closely match the numerical solutions of the equations and accurately predict the extent to which oxygen can diffuse. The derived expressions relate the limit to which oxygen can diffuse into a tissue to the OCR of that tissue. We also demonstrate that differences between these functional forms are likely to be negligible within the range of literature estimates of the hyperbolic oxygen constant, suggesting that the constant consumption rate approximation suffices for modelling oxygen dynamics for most values of OCR. These approximations also allow the rapid identification of situations where hyperbolic consumption forms can result in significant differences from constant consumption rate models, and so can reduce the computational workload associated with numerical solutions, by estimating both the oxygen diffusion distances and resultant oxygen profile. Such analysis may be useful for parameter fitting in large imaging datasets and histological sections, and allows easy quantification of projected differences between functional forms of OCR.

Dataset Information

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

Publications

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

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