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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 5

Increased cell death and pyroptosis in old hematopoietic progenitors.

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Increased cell death and pyroptosis in old hematopoietic progenitors.
(A...
(A) Frequency of dead cells among TLPs (using LIVE/DEAD staining assay) at 7, 14, 21, and 28 days upon in vitro differentiation of FACS-isolated CD34+ HPCs from young (Y, n = 9) or old (O, n = 10) healthy adults in the OP9-DL1 coculture system. (B) Representative image and staining levels for annexin V and PI in bead-enriched CD34+ cells from young (n = 5) or old adult (n = 5) PBMCs. (C) Increased mRNA expression of the proapoptotic gene P2X7 in FACS-isolated HPCs from old (n = 10) healthy adults compared with HPCs from young (n = 7) subjects. (D) Representative staining and expression levels of cleaved caspase 1 in CD34+ cells from young (n = 5) or old (n = 5) adult PBMCs. Data are expressed as ratio of stimulated versus unstimulated cells. Bars indicate the median. (E) Enhancement of in vitro survival of TLPs at 14 or 21 days in the presence of PPAD (P2X7 inhibitor, at 20 μM) or VX-765 (caspase 1 inhibitor, at 0.1 μM) from day 7 in the OP9-DL1 culture system. Survival is expressed as the ratio of dying cells at day 14 or 21 over day 7 in culture (n = 5 in the presence of PPAD or VX-765 and n = 10 in the absence of inhibitors). Columns indicate mean (+SEM). The Mann-Whitney test was used for comparisons.

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