HbF Levels in Sickle Cell Disease Are Associated with Proportion of Circulating Hematopoietic Stem and Progenitor Cells and CC-Chemokines.

Caterina P Minniti,Karl Robert,Zi Yan,Andrew S Crouch,Kai Wang,Shouping Zhang,Eric E Bouhassira,Joan Uehlinger,Deepa Manwani,Seda S Tolu

doi:10.3390/cells9102199

Caterina P Minniti, Karl Robert + Show 8 more

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https://doi.org/10.3390/cells9102199

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Abstract

The concentration of circulating hematopoietic stem and progenitor cells has not been studied longitudinally. Here, we report that the proportions of Lin-CD34+38- hematopoietic multipotent cells (HMCs) and of Lin-CD34+CD38+ hematopoietic progenitors cells (HPCs) are highly variable between individuals but stable over long periods of time, in both healthy individuals and sickle cell disease (SCD) patients. This suggests that these proportions are regulated by genetic polymorphisms or by epigenetic mechanisms. We also report that in SCD patients treated with hydroxyurea, the proportions of circulating HMCs and HPCs show a strong positive and negative correlation with fetal hemoglobin (HbF) levels, respectively. Titration of 65 cytokines revealed that the plasma concentration of chemokines CCL2, CCL11, CCL17, CCL24, CCL27, and PDGF-BB were highly correlated with the proportion of HMCs and HPCs and that a subset of these cytokines were also correlated with HbF levels. A linear model based on four of these chemokines could explain 80% of the variability in the proportion of circulating HMCs between individuals. The proportion of circulating HMCs and HPCs and the concentration of these chemokines might therefore become useful biomarkers for HbF response to HU in SCD patients. Such markers might become increasingly clinically relevant, as alternative treatment modalities for SCD are becoming available.

Highlights

Sickle cell disease (SCD) is a single-point mutation from glutamic acid to valine that results in pleomorphic clinical complications caused by polymerization of hemoglobin S (HbS) and its downstream vaso-occlusive complications, many of which increase with age [1,2]
We report that the proportions of circulating stem and progenitor cells are highly variable between individuals, but highly stable over time. We report that these proportions of stem and progenitor cells are highly correlated with HbF levels in HU treated patients and with plasma concentrations of several chemokines
Cell compartment are referred to asstem cells multipotent cells (HMCs), which include 49f+progenitors long-term hematopoietic stemlymphoid-primed cells (LT(LT-HSCs),hematopoietic hematopoietic stem cells (HSCs), multipotent (MPPs), and

Summary

Introduction

Sickle cell disease (SCD) is a single-point mutation from glutamic acid to valine that results in pleomorphic clinical complications caused by polymerization of hemoglobin S (HbS) and its downstream vaso-occlusive complications, many of which increase with age [1,2]. SCD currently affects 25 million people worldwide, a number projected to increase by 30% in 2050 [4,5]. The current therapies for SCD involve treatment with either hydroxyurea (HU) or transfusion. In addition to HU, several drugs based on decreasing HbS polymerization are in development or were recently approved [6,7]. Whether they will prove complementary or more efficacious than the current standard of therapy with HU is uncertain at this time. Understanding the mechanism of action of HU and finding additional drugs to increase fetal hemoglobin production, remain priorities in the treatment of SCD

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