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Barcoding blood stem cells reveals their secrets
By tagging bone marrow cells with a genetic label — or barcode — researchers are able to describe and follow individual cells as they form inside a mouse. The scientists discovered these blood cells regenerate differently than their counterparts from blood cell transplants. Published in the Jan. 3 issue of Nature, the work was funded by the National Heart, Lung and Blood Institute (NHLBI), part of the National Institutes of Health.
"The findings of this research, if applicable to humans, will have implications for blood cell transplantation, and for clinical and research methods using blood cells, such as gene therapy or gene editing," John W. Thomas PhD, Stem Cell and Cell-based Therapy Coordinator at NHLBI.
The study moves research a step further towards the development of blood regeneration therapies. Researchers also believe it is applicable to a variety of cells and will yield insights for regenerating diseased or damaged tissues.
"Our results show that stem cells and their less pluripotent descendants, blood progenitor cells, behave somewhat differently when studied without removal from their native environment. Studied in a laboratory or during transplantation leads to differences in the types of blood lineages," says Alejo Rodriguez Fraticelli PhD, Harvard Stem Cell Institute at Boston Children's Hospital, and study first author.
Due to the lack of tools for studying how blood forms in the body, the majority of studies are done after blood transplant. In that context, transplanted cells have been "perturbed" or removed from their natural environment. According to researchers, the current models are more likely to represent a roadmap of lineage potential for the natural offspring of blood cells.
For Rodriguez Fraticelli, the research highlights the importance of studying blood regeneration in its native context: "Moving forward, we need to come up with methods to better predict what types of cells will be the most optimal for therapy, for instance in reprogramming and editing cells."
In the study, researchers tagged cells using a transposon, a piece of genetic code that can jump to a random point in DNA when exposed to an enzyme called transposase, to track blood progenitors and adult stem cells during the natural, unperturbed process of blood regeneration.
Today's research provides evidence for a substantially revised roadmap of normal blood regeneration or blood production in a natural environment. It also highlights how under natural conditions, blood stem cells and progenitor cells manifest unique properties.
Haematopoiesis, the process of mature blood and immune cell production, is functionally organized as a hierarchy, with self-renewing haematopoietic stem cells and multipotent progenitor cells sitting at the very top 1,2. Multiple models have been proposed as to what the earliest lineage choices are in these primitive haematopoietic compartments, the cellular intermediates, and the resulting lineage trees that emerge from them 3,4,5,6,7,8,9,10. Given that the bulk of studies addressing lineage outcomes have been performed in the context of haematopoietic transplantation, current models of lineage branching are more likely to represent roadmaps of lineage potential than native fate. Here we use transposon tagging to clonally trace the fates of progenitors and stem cells in unperturbed haematopoiesis. Our results describe a distinct clonal roadmap in which the megakaryocyte lineage arises largely independently of other haematopoietic fates. Our data, combined with single-cell RNA sequencing, identify a functional hierarchy of unilineage- and oligolineage-producing clones within the multipotent progenitor population. Finally, our results demonstrate that traditionally defined long-term haematopoietic stem cells are a significant source of megakaryocyte-restricted progenitors, suggesting that the megakaryocyte lineage is the predominant native fate of long-term haematopoietic stem cells. Our study provides evidence for a substantially revised roadmap for unperturbed haematopoiesis, and highlights unique properties of multipotent progenitors and haematopoietic stem cells in situ.
Authors: Alejo E. Rodriguez-Fraticelli, Samuel L. Wolock, Caleb S. Weinreb, Riccardo Panero, Sachin H. Patel, Maja Jankovic, Jianlong Sun, Raffaele A. Calogero, Allon M. Klein and Fernando D. Camargo
Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at http://www.nhlbi.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
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Lineage fate of blood cell haematopoiesis — the process by which mature blood and immune cells form. Multipotent long-term HSCs (LT-HSCs) reside in the bone marrow. Hematopoietic multipotent progenitor (MPP) refers to a class of hematopoietic stem cells that have lost their self-renewal capacity but remain multipotent and can differentiate into all mature cell types found in the blood.
Image credit: Courtesy of the Stem Cell Program, Boston Children’s Hospital.