Live-animal imaging of native haematopoietic stem and progenitor cells

Constantina Christodoulou, Joel A. Spencer, Shu-Chi A. Yeh, Raphaël Turcotte, Konstantinos D. Kokkaliaris, Riccardo Panero, Azucena Ramos, Guoji Guo, Negar Seyedhassantehrani, Tatiana V. Esipova, Sergei A. Vinogradov, Sarah Rudzinskas, Yi Zhang, Archibald S. Perkins, Stuart H. Orkin, Raffaele A. Calogero, Timm Schroeder, Charles P. Lin () and Fernando D. Camargo ()
Additional contact information
Constantina Christodoulou: Boston Children’s Hospital
Joel A. Spencer: Massachusetts General Hospital
Shu-Chi A. Yeh: Massachusetts General Hospital
Raphaël Turcotte: Massachusetts General Hospital
Konstantinos D. Kokkaliaris: ETH Zurich
Riccardo Panero: University of Torino
Azucena Ramos: Boston Children’s Hospital
Guoji Guo: Howard Hughes Medical Institute, Harvard Medical School
Negar Seyedhassantehrani: University of California Merced
Tatiana V. Esipova: University of Pennsylvania
Sergei A. Vinogradov: University of Pennsylvania
Sarah Rudzinskas: University of Rochester Medical Center
Yi Zhang: University of Rochester Medical Center
Archibald S. Perkins: University of Rochester Medical Center
Stuart H. Orkin: Howard Hughes Medical Institute, Harvard Medical School
Raffaele A. Calogero: University of Torino
Timm Schroeder: ETH Zurich
Charles P. Lin: Massachusetts General Hospital
Fernando D. Camargo: Boston Children’s Hospital

Nature, 2020, vol. 578, issue 7794, 278-283

Abstract: Abstract The biology of haematopoietic stem cells (HSCs) has predominantly been studied under transplantation conditions1,2. 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 marrow3–5. 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.

Date: 2020
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DOI: 10.1038/s41586-020-1971-z

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