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Aryl hydrocarbon receptor may play role in red blood cell development
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Modulation of the aryl hydrocarbon receptor was associated with significant production of hematopoietic progenitor cells in vitro, according to study results.
Several researchers from Boston and Philadelphia have demonstrated that the aryl hydrocarbon receptor may regulate the hematopoietic and immune systems during development in a cell-specific manner.
An in vitro model system that allows the production of primary human hematopoietic progenitor cells that have the capacity to differentiate into megakaryocyte- and erythroid-lineage cells facilitated the current study. Researchers aimed to determine whether aryl hydrocarbon receptor modulation could facilitate the expansion of progenitor cells and the differentiation of megakaryocyte and erythroid cells.
Study protocols called for the use of a novel induced pluripotent stem cell (iPSC)-based, chemically defined serum and a feeder cell-free culture system.
Results indicated that functional human hematopoietic progenitor cells express the aryl hydrocarbon receptor, and that activation of this receptor in hematopoietic progenitor cells drives an expansion of the progenitor cells, along with megakaryocyte- and erythroid-lineage cells.
Modulating the aryl hydrocarbon receptor further within the expanding populations of the progenitor cells dictated cell fate with chronic agonism of the receptor permissive to erythroid differentiation and acute antagonism favoring megakaryocyte specification.
George J. Murphy
“These results highlight the development of a new, GMP-compliant platform for generating virtually unlimited numbers of human [hematopoietic progenitor cells] with which to scrutinize red blood cell and platelet development, including the assessment of the role of this environmental chemical receptor in critical cell fate decisions during hematopoiesis,” the researchers concluded.
“This finding has enabled us to overcome a major hurdle in terms of being able to produce enough of these cells to have a potential therapeutic impact both in the lab and, down the line, in patients,” George J. Murphy, PhD, assistant professor of medicine at Boston University School of Public Health and co-director of the Center for Regenerative Medicine at Boston University, said in a press release. “Additionally, our work suggests that [aryl hydrocarbon receptor] has a very important biological function in how blood cells form in the body.”
Perspective
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H. Franklin Bunn, MD
The journal Blood faces the challenge of publishing papers aimed at a broad array of readers, ranging from basic scientists to clinicians. The paper by Smith, Rozelle, Murphy and colleagues has considerable appeal and relevance to both groups.
They have extended previous work of others on a transcription factor, the aryl hydrocarbon receptor (AhR), showing that it plays a key role in hematopoiesis, as well as in erythroid and megakaryocyte development. Moreover, they describe an experimental platform that could be exploited for in vitro production of hematopoietic progenitors in amounts sufficient for patient administration.
The AhR is a transcription factor that binds to a wide range of organic molecules, enabling transcriptional induction of genes such as P450 cytochromes that protect the body from xenobiotic toxicity. Smith and colleagues show that — although the expression of AhR is very low in hematopoietic stem cells — when the receptor is activated by certain ligands, there is enhanced cell proliferation and suppression of apoptosis. This results in a stunning enhancement of progenitors, primarily erythroid and megakaryocytic.
These studies raise the realistic possibility that pluripotent stem cells induced from skin fibroblasts or peripheral blood of a patient could be cultured in the presence of hematopoietic cytokines and a selected hydrocarbon that activates the AhR to yield a logarithmic expansion of hematopoietic progenitor and precursor cells sufficient for in vivo transplantation.
Of course, considerable hurdles must first be overcome, including demonstration that the circulating progeny of these cells are viable and functional. But if this lofty aim comes to fruition, it could fulfill crucial and daunting clinical challenges, such as patients refractory to conventional red cell and platelet transfusions.
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