Shape-Shifted Red Blood Cells: A Novel Red Blood Cell Stage?

Verónica Chico,María Ortega-Villaizan,Julio Coll,Alberto Villena,Luis Mercado,Iván Nombela,Begoña Carracedo,María Mena,Sergio Ciordia,Sara Puente-Marin

doi:10.3390/cells7040031

Abstract

Primitive nucleated erythroid cells in the bloodstream have long been suggested to be more similar to nucleated red cells of fish, amphibians, and birds than the red cells of fetal and adult mammals. Rainbow trout Ficoll-purified red blood cells (RBCs) cultured in vitro undergo morphological changes, especially when exposed to stress, and enter a new cell stage that we have coined shape-shifted RBCs (shRBCs). We have characterized these shRBCs using transmission electron microscopy (TEM) micrographs, Wright–Giemsa staining, cell marker immunostaining, and transcriptomic and proteomic evaluation. shRBCs showed reduced density of the cytoplasm, hemoglobin loss, decondensed chromatin in the nucleus, and striking expression of the B lymphocyte molecular marker IgM. In addition, shRBCs shared some features of mammalian primitive pyrenocytes (extruded nucleus surrounded by a thin rim of cytoplasm and phosphatidylserine (PS) exposure on cell surface). These shRBCs were transiently observed in heat-stressed rainbow trout bloodstream for three days. Functional network analysis of combined transcriptomic and proteomic studies resulted in the identification of proteins involved in pathways related to the regulation of cell morphogenesis involved in differentiation, cellular response to stress, and immune system process. In addition, shRBCs increased interleukin 8 (IL8), interleukin 1 β (IL1β), interferon ɣ (IFNɣ), and natural killer enhancing factor (NKEF) protein production in response to viral hemorrhagic septicemia virus (VHSV). In conclusion, shRBCs may represent a novel cell stage that participates in roles related to immune response mediation, homeostasis, and the differentiation and development of blood cells.

Highlights

It has recently come to light that nucleated red blood cells (RBCs) of fish are multifunctional cells, because in addition to being involved in gas exchange and transport, it has been reported that they respond to pathogens
In order to determine a physiological condition that triggered the morphological transformation process, Ficoll-purified RBCs were incubated at different temperatures (14 ◦ C, 25 ◦ C and 28 ◦ C), because we had previously observed that high temperatures alter rainbow trout RBC morphology
RBCs vitro undergo morphological changes vitro varied individuals, but theircultured generationin is evident when RBCs are exposed to some types to a new temperature, mechanical or chemical stimulation. evolution shifted RBCs (shRBCs) are characterized a shRBCs cell stage of orstress, typesuch thataswe have termed shRBCs

Summary

Introduction

It has recently come to light that nucleated red blood cells (RBCs) of fish are multifunctional cells, because in addition to being involved in gas exchange and transport, it has been reported that they respond to pathogens. Rainbow trout RBCs have been described to exert paracrine molecular antiviral communication with other cells [6]. This evidence indicates that fish RBCs importantly contribute to immune response to infections [8]. Human cord blood nucleated RBCs have been shown to exert a regulatory function in the innate immune response, by means of the suppression of the production of inflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin

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Results

Conclusion