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

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 1

Altered lymphopoietic capacity of circulating CD34+ hematopoietic progenitors from elderly humans.

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Altered lymphopoietic capacity of circulating CD34+ hematopoietic progen...
(A) Representative examples of CD34 and CD45 staining to identify HPCs within the CD45lo population. (B) Absolute counts of CD34+CD45loLin– cells in young (Y, n = 20), middle-aged (M, n = 35), or old (O, n = 40) healthy adults. (C) Representative staining for CD38, CD90, CD117, CD45RA, and CD10 on bead-enriched CD34+ cells from PBMCs of a healthy adult. (D) Ratio of common lymphoid progenitors (CLPs, CD38+CD117–CD45RA+CD10+) versus common myeloid progenitors (CMPs, CD38+CD117+CD45RA–CD10–) within CD34+ cells from PBMCs in young, middle-aged, or old healthy adults. (E) Frequency of CLPs or CMPs in the blood of young, middle-aged, or old healthy adults. (F) Frequency of TLPs upon in vitro differentiation of FACS-isolated CD34+ HPCs from young (n = 9) or old (n = 10) healthy adults. Phenotyping of CD34+ cells was performed after 7, 14, 21, and 28 days in the OP9-DL1 coculture system. (G) Mean absolute counts of TLPs in culture upon in vitro differentiation of CD34+ HPCs purified from young (n = 9) or old (n = 10) healthy adults in the OP9-DL1 coculture system. (H) Distribution of TLP subsets of differentiation (ProT1: CD45RA+CD7+CD5–CD1a–; ProT2: CD45RA+CD7+CD5+CD1a–; PreTimmature: CD45RA+CD7+CD5–CD1a+; and PreT1: CD45RA+CD7+CD5+CD1a+) at 7, 14, 21, and 28 days in the OP9-DL1 coculture system. Columns indicate mean values (+SEM). (I) Percentages of TLP subsets within the total population in vitro are represented in pie charts for simplicity (black slices correspond to proT1, dark gray to proT2, light gray to preTimmature, and white to preT1). Pies show mean values. The Mann-Whitney or Kruskall-Wallis test was used for comparing 2 or 3 groups, respectively. Bars indicate the median.