Live-animal imaging of native haematopoietic stem and progenitor cells

The biology of haematopoietic stem cells (HSCs) has predominantly been studied under transplantation conditions 1 , 2 . It has been particularly challenging to study dynamic HSC behaviour, given that the visualization of HSCs in the native niche in live animals has not, to our knowledge, been achiev...

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Veröffentlicht in:Nature (London) 2020-02, Vol.578 (7794), p.278-283
Hauptverfasser: Christodoulou, Constantina, Spencer, Joel A., Yeh, Shu-Chi A., Turcotte, Raphaël, Kokkaliaris, Konstantinos D., Panero, Riccardo, Ramos, Azucena, Guo, Guoji, Seyedhassantehrani, Negar, Esipova, Tatiana V., Vinogradov, Sergei A., Rudzinskas, Sarah, Zhang, Yi, Perkins, Archibald S., Orkin, Stuart H., Calogero, Raffaele A., Schroeder, Timm, Lin, Charles P., Camargo, Fernando D.
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container_end_page 283
container_issue 7794
container_start_page 278
container_title Nature (London)
container_volume 578
creator Christodoulou, Constantina
Spencer, Joel A.
Yeh, Shu-Chi A.
Turcotte, Raphaël
Kokkaliaris, Konstantinos D.
Panero, Riccardo
Ramos, Azucena
Guo, Guoji
Seyedhassantehrani, Negar
Esipova, Tatiana V.
Vinogradov, Sergei A.
Rudzinskas, Sarah
Zhang, Yi
Perkins, Archibald S.
Orkin, Stuart H.
Calogero, Raffaele A.
Schroeder, Timm
Lin, Charles P.
Camargo, Fernando D.
description The biology of haematopoietic stem cells (HSCs) has predominantly been studied under transplantation conditions 1 , 2 . It has been particularly challenging to study dynamic HSC behaviour, given that the visualization of HSCs in the native niche in live animals has not, to our knowledge, been achieved. Here we describe a dual genetic strategy in mice that restricts reporter labelling to a subset of the most quiescent long-term HSCs (LT-HSCs) and that is compatible with current intravital imaging approaches in the calvarial bone marrow 3 – 5 . We show that this subset of LT-HSCs resides close to both sinusoidal blood vessels and the endosteal surface. By contrast, multipotent progenitor cells (MPPs) show greater variation in distance from the endosteum and are more likely to be associated with transition zone vessels. LT-HSCs are not found in bone marrow niches with the deepest hypoxia and instead are found in hypoxic environments similar to those of MPPs. In vivo time-lapse imaging revealed that LT-HSCs at steady-state show limited motility. Activated LT-HSCs show heterogeneous responses, with some cells becoming highly motile and a fraction of HSCs expanding clonally within spatially restricted domains. These domains have defined characteristics, as HSC expansion is found almost exclusively in a subset of bone marrow cavities with bone-remodelling activity. By contrast, cavities with low bone-resorbing activity do not harbour expanding HSCs. These findings point to previously unknown heterogeneity within the bone marrow microenvironment, imposed by the stages of bone turnover. Our approach enables the direct visualization of HSC behaviours and dissection of heterogeneity in HSC niches. A dual genetic strategy enables the labelling and in vivo imaging of native long-term haematopoietic stem cells in the mouse calvarial bone marrow.
doi_str_mv 10.1038/s41586-020-1971-z
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It has been particularly challenging to study dynamic HSC behaviour, given that the visualization of HSCs in the native niche in live animals has not, to our knowledge, been achieved. Here we describe a dual genetic strategy in mice that restricts reporter labelling to a subset of the most quiescent long-term HSCs (LT-HSCs) and that is compatible with current intravital imaging approaches in the calvarial bone marrow 3 – 5 . We show that this subset of LT-HSCs resides close to both sinusoidal blood vessels and the endosteal surface. By contrast, multipotent progenitor cells (MPPs) show greater variation in distance from the endosteum and are more likely to be associated with transition zone vessels. LT-HSCs are not found in bone marrow niches with the deepest hypoxia and instead are found in hypoxic environments similar to those of MPPs. In vivo time-lapse imaging revealed that LT-HSCs at steady-state show limited motility. Activated LT-HSCs show heterogeneous responses, with some cells becoming highly motile and a fraction of HSCs expanding clonally within spatially restricted domains. These domains have defined characteristics, as HSC expansion is found almost exclusively in a subset of bone marrow cavities with bone-remodelling activity. By contrast, cavities with low bone-resorbing activity do not harbour expanding HSCs. These findings point to previously unknown heterogeneity within the bone marrow microenvironment, imposed by the stages of bone turnover. Our approach enables the direct visualization of HSC behaviours and dissection of heterogeneity in HSC niches. 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Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Earth, Atmospheric &amp; Aquatic Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>ProQuest Health &amp; Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health &amp; Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied &amp; Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>University of Michigan</collection><collection>Genetics Abstracts</collection><collection>SIRS Editorial</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Christodoulou, Constantina</au><au>Spencer, Joel A.</au><au>Yeh, Shu-Chi A.</au><au>Turcotte, Raphaël</au><au>Kokkaliaris, Konstantinos D.</au><au>Panero, Riccardo</au><au>Ramos, Azucena</au><au>Guo, Guoji</au><au>Seyedhassantehrani, Negar</au><au>Esipova, Tatiana V.</au><au>Vinogradov, Sergei A.</au><au>Rudzinskas, Sarah</au><au>Zhang, Yi</au><au>Perkins, Archibald S.</au><au>Orkin, Stuart H.</au><au>Calogero, Raffaele A.</au><au>Schroeder, Timm</au><au>Lin, Charles P.</au><au>Camargo, Fernando D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Live-animal imaging of native haematopoietic stem and progenitor cells</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2020-02-13</date><risdate>2020</risdate><volume>578</volume><issue>7794</issue><spage>278</spage><epage>283</epage><pages>278-283</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>The biology of haematopoietic stem cells (HSCs) has predominantly been studied under transplantation conditions 1 , 2 . It has been particularly challenging to study dynamic HSC behaviour, given that the visualization of HSCs in the native niche in live animals has not, to our knowledge, been achieved. Here we describe a dual genetic strategy in mice that restricts reporter labelling to a subset of the most quiescent long-term HSCs (LT-HSCs) and that is compatible with current intravital imaging approaches in the calvarial bone marrow 3 – 5 . We show that this subset of LT-HSCs resides close to both sinusoidal blood vessels and the endosteal surface. By contrast, multipotent progenitor cells (MPPs) show greater variation in distance from the endosteum and are more likely to be associated with transition zone vessels. LT-HSCs are not found in bone marrow niches with the deepest hypoxia and instead are found in hypoxic environments similar to those of MPPs. In vivo time-lapse imaging revealed that LT-HSCs at steady-state show limited motility. Activated LT-HSCs show heterogeneous responses, with some cells becoming highly motile and a fraction of HSCs expanding clonally within spatially restricted domains. These domains have defined characteristics, as HSC expansion is found almost exclusively in a subset of bone marrow cavities with bone-remodelling activity. By contrast, cavities with low bone-resorbing activity do not harbour expanding HSCs. These findings point to previously unknown heterogeneity within the bone marrow microenvironment, imposed by the stages of bone turnover. Our approach enables the direct visualization of HSC behaviours and dissection of heterogeneity in HSC niches. A dual genetic strategy enables the labelling and in vivo imaging of native long-term haematopoietic stem cells in the mouse calvarial bone marrow.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32025033</pmid><doi>10.1038/s41586-020-1971-z</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record>
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identifier ISSN: 0028-0836
ispartof Nature (London), 2020-02, Vol.578 (7794), p.278-283
issn 0028-0836
1476-4687
language eng
recordid cdi_proquest_miscellaneous_2352050175
source MEDLINE; SpringerLink Journals; Nature Journals Online
subjects 13
13/100
13/31
14/19
14/69
38
38/62
38/91
631/1647/245/2186
631/532/1542
64/60
Analysis
Animals
Blood vessels
Bone imaging
Bone marrow
Bone Remodeling
Bone turnover
Cell cycle
Cell Movement
Cell Proliferation
Cell Survival
Domains
Female
fms-Like Tyrosine Kinase 3 - genetics
fms-Like Tyrosine Kinase 3 - metabolism
Genes, Reporter
Hematopoietic stem cells
Hematopoietic Stem Cells - metabolism
Hemopoiesis
Heterogeneity
Humanities and Social Sciences
Hypoxia
Hypoxia - metabolism
Imaging
Imaging systems
Labeling
Localization
Male
MDS1 and EVI1 Complex Locus Protein - genetics
MDS1 and EVI1 Complex Locus Protein - metabolism
Methods
Mice
Molecular Imaging
multidisciplinary
Oxygen - metabolism
Population
Progenitor cells
Science
Science (multidisciplinary)
Skull - cytology
Stem cell transplantation
Stem cells
Transplantation
Transplants & implants
Visualization
title Live-animal imaging of native haematopoietic stem and progenitor cells
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