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Elderly human hematopoietic progenitor cells express cellular senescence markers and are more susceptible to pyroptosis
Tinhinane Fali, … , Delphine Sauce, Victor Appay
Tinhinane Fali, … , Delphine Sauce, Victor Appay
Published July 12, 2018
Citation Information: JCI Insight. 2018;3(13):e95319. https://doi.org/10.1172/jci.insight.95319.
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Research Article Aging Stem cells

Elderly human hematopoietic progenitor cells express cellular senescence markers and are more susceptible to pyroptosis

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Abstract

The maintenance of effective immunity over time is dependent on the capacity of hematopoietic stem cells (HSCs) to sustain the pool of immunocompetent mature cells. Decline of immune competence with old age may stem from HSC defects, including reduced self-renewal potential and impaired lymphopoiesis, as suggested in murine models. To obtain further insights into aging-related alteration of hematopoiesis, we performed a comprehensive study of blood hematopoietic progenitor cells (HPCs) from older humans. In the elderly, HPCs present active oxidative phosphorylation and are pressed to enter cell cycling. However, p53-p21 and p15 cell senescence pathways, associated with telomerase activity deficiency, strong telomere attrition, and oxidative stress, are engaged, thus limiting cell cycling. Moreover, survival of old HPCs is impacted by pyroptosis, an inflammatory form of programmed cell death. Lastly, telomerase activity deficiency and telomere length attrition of old HPCs may be passed on to progeny cells such as naive T lymphocytes, further highlighting the poor hematopoietic potential of the elderly. This pre-senescent profile is characteristic of the multiple intrinsic and extrinsic factors affecting HPCs in elderly individuals and represents a major obstacle in terms of immune reconstitution and efficacy with advanced age.

Authors

Tinhinane Fali, Véronique Fabre-Mersseman, Takuya Yamamoto, Charles Bayard, Laura Papagno, Solène Fastenackels, Rima Zoorab, Richard A. Koup, Jacques Boddaert, Delphine Sauce, Victor Appay

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Figure 3

Upregulated mTOR pathway and mitochondrial stress in old hematopoietic progenitors.

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Upregulated mTOR pathway and mitochondrial stress in old hematopoietic p...
(A) mRNA expression levels of the Wnt pathway–related genes TCF7, LEF1, and FZD3 in FACS-isolated HPCs from young (Y, n = 7) or old (O, n = 10) subjects. (B) mRNA expression levels of the mTOR pathway–related genes mTOR and S6K in FACS-isolated HPCs from young (n = 6) or old (n = 10) subjects. (C) Representative staining and median fluorescence intensity (MFI) levels for phosphorylated S6K in bead-enriched CD34+ cells from young or old adult PBMCs. (D and E) Representative staining and MFI levels of MitoTracker (mitochondrial mass marker) and CellRox (cellular ROS marker) in bead-enriched CD34+ cells from young or old adult PBMCs. (F and G) mRNA expression levels of genes associated with mitochondrial protein folding stress (CLPP, CLPX, and LON) and mitochondrial stress response (HSP60, HSP70) in FACS-isolated HPCs from young (n = 6) or old (n = 9) subjects. (H) Frequency of young or old CD34+ cells expressing the nuclear antigen Ki67. (I) Representative staining for Ki67 in CD3+ or CD34+ cells from an elderly individual, highlighting differential Ki67 expression levels. The Mann-Whitney test was used for comparisons. Bars indicate the median.

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