Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment

Ryo Yamamoto; Adam C Wilkinson; Jun Ooehara; Xun Lan; Chen-Yi Lai; Yusuke Nakauchi; Jonathan K Pritchard; Hiromitsu Nakauchi

doi:10.1016/j.stem.2018.03.013

Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment

Cell Stem Cell. 2018 Apr 5;22(4):600-607.e4. doi: 10.1016/j.stem.2018.03.013.

Authors

Ryo Yamamoto¹, Adam C Wilkinson², Jun Ooehara³, Xun Lan⁴, Chen-Yi Lai³, Yusuke Nakauchi³, Jonathan K Pritchard⁵, Hiromitsu Nakauchi⁶

Affiliations

¹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA; Division of Stem Cell Therapy, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
² Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
³ Division of Stem Cell Therapy, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
⁴ Department of Genetics, Stanford University, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
⁵ Department of Genetics, Stanford University, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
⁶ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA; Division of Stem Cell Therapy, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. Electronic address: [email protected].

Abstract

Aging is linked to functional deterioration and hematological diseases. The hematopoietic system is maintained by hematopoietic stem cells (HSCs), and dysfunction within the HSC compartment is thought to be a key mechanism underlying age-related hematopoietic perturbations. Using single-cell transplantation assays with five blood-lineage analysis, we previously identified myeloid-restricted repopulating progenitors (MyRPs) within the phenotypic HSC compartment in young mice. Here, we determined the age-related functional changes to the HSC compartment using over 400 single-cell transplantation assays. Notably, MyRP frequency increased dramatically with age, while multipotent HSCs expanded modestly within the bone marrow. We also identified a subset of functional cells that were myeloid restricted in primary recipients but displayed multipotent (five blood-lineage) output in secondary recipients. We have termed this cell type latent-HSCs, which appear exclusive to the aged HSC compartment. These results question the traditional dogma of HSC aging and our current approaches to assay and define HSCs.

Keywords: HSC; aging; clonal analysis; hematopoiesis; hematopoietic stem cell; multipotency; self-renewal; single cell; stem cell aging.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging*
Animals
Hematopoietic Stem Cell Transplantation*
Hematopoietic Stem Cells / cytology*
Mice

Abstract

Publication types

MeSH terms

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