Top

Immunity & Ageing

Published in:

Open Access 01-12-2020 | Research

ARID3a expression in human hematopoietic stem cells is associated with distinct gene patterns in aged individuals

Authors: Michelle L. Ratliff, Joshua Garton, Judith A. James, Carol F. Webb

Published in: Immunity & Ageing | Issue 1/2020

Abstract

Background

Immunologic aging leads to immune dysfunction, significantly reducing the quality of life of the elderly. Aged-related defects in early hematopoiesis result in reduced lymphoid cell development, functionally defective mature immune cells, and poor protective responses to vaccines and pathogens. Despite considerable progress understanding the underlying causes of decreased immunity in the elderly, the mechanisms by which these occur are still poorly understood. The DNA-binding protein ARID3a is expressed in a subset of human hematopoietic progenitors. Inhibition of ARID3a in bulk human cord blood CD34⁺ hematopoietic progenitors led to developmental skewing toward myeloid lineage at the expense of lymphoid lineage cells in vitro. Effects of ARID3a expression in adult-derived hematopoietic stem cells (HSCs) have not been analyzed, nor has ARID3a expression been assessed in relationship to age. We hypothesized that decreases in ARID3a could explain some of the defects observed in aging.

Results

Our data reveal decreased frequencies of ARID3a-expressing peripheral blood HSCs from aged healthy individuals compared with young donor HSCs. Inhibition of ARID3a in young donor-derived HSCs limits B lineage potential, suggesting a role for ARID3a in B lymphopoiesis in bone marrow-derived HSCs. Increasing ARID3a levels of HSCs from aged donors in vitro alters B lineage development and maturation. Finally, single cell analyses of ARID3a-expressing HSCs from young versus aged donors identify a number of differentially expressed genes in aged ARID3A-expressing cells versus young ARID3A-expressing HSCs, as well as between ARID3A-expressing and non-expressing cells in both young and aged donor HSCs.

Conclusions

These data suggest that ARID3a-expressing HSCs from aged individuals differ at both molecular and functional levels compared to ARID3a-expressing HSCs from young individuals.

Colby SL, Ortman JM. Projections of the Size and Composition of the U.S. Population: 2014 to 2060. Population Estimates and Projections. Current Population Reports. P25–1143. Numerical/Quantitative Data Report. Washington, DC: US Census Bureau; 2015. Tel: 800–923-8282; Tel: 301–763-4636; e-mail: Census.in.Schools@census.gov; Web site: http://www.census.gov/; Report No.: ED578934.

Pang WW, Schrier SL, Weissman IL. Age-associated changes in human hematopoietic stem cells. Semin Hematol. 2017;54(1):39–42.PubMed

Laurenti E, Gottgens B. From haematopoietic stem cells to complex differentiation landscapes. Nature. 2018;553(7689):418–26.PubMedPubMedCentral

Dykstra B, Olthof S, Schreuder J, Ritsema M, de Haan G. Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J Exp Med. 2011;208(13):2691–703.PubMedPubMedCentral

Kuranda K, Vargaftig J, de la Rochere P, Dosquet C, Charron D, Bardin F, et al. Age-related changes in human hematopoietic stem/progenitor cells. Aging Cell. 2011;10(3):542–6.PubMed

Pang WW, Price EA, Sahoo D, Beerman I, Maloney WJ, Rossi DJ, et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci U S A. 2011;108(50):20012–7.PubMedPubMedCentral

Sun D, Luo M, Jeong M, Rodriguez B, Xia Z, Hannah R, et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell. 2014;14(5):673–88.PubMedPubMedCentral

Fali T, Fabre-Mersseman V, Yamamoto T, Bayard C, Papagno L, Fastenackels S, et al. Elderly human hematopoietic progenitor cells express cellular senescence markers and are more susceptible to pyroptosis. JCI Insight. 2018;3(13):e95319.PubMedCentral

Flach J, Bakker ST, Mohrin M, Conroy PC, Pietras EM, Reynaud D, et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature. 2014;512(7513):198–202.PubMedPubMedCentral

10.

Kortschak RD, Tucker PW, Saint R. ARID proteins come in from the desert. Trends Biochem Sci. 2000;25(6):294–9.PubMed

11.

Patsialou A, Wilsker D, Moran E. DNA-binding properties of ARID family proteins. Nucleic Acids Res. 2005;33(1):66–80.PubMedPubMedCentral

12.

Ratliff ML, Templeton TD, Ward JM, Webb CF. The bright side of hematopoiesis: regulatory roles of ARID3a/bright in human and mouse hematopoiesis. Front Immunol. 2014;5:113.PubMedPubMedCentral

13.

Popowski M, Templeton TD, Lee BK, Rhee C, Li H, Miner C, et al. Bright/Arid3A acts as a barrier to somatic cell reprogramming through direct regulation of Oct4, Sox2, and Nanog. Stem Cell Rep. 2014;2(1):26–35.

14.

Rajaiya J, Nixon JC, Ayers N, Desgranges ZP, Roy AL, Webb CF. Induction of immunoglobulin heavy-chain transcription through the transcription factor bright requires TFII-I. Mol Cell Biol. 2006;26(12):4758–68.PubMedPubMedCentral

15.

Rajaiya J, Hatfield M, Nixon JC, Rawlings DJ, Webb CF. Bruton’s tyrosine kinase regulates immunoglobulin promoter activation in association with the transcription factor bright. Mol Cell Biol. 2005;25(6):2073–84.PubMedPubMedCentral

16.

Lin D, Ippolito GC, Zong RT, Bryant J, Koslovsky J, Tucker P. Bright/ARID3A contributes to chromatin accessibility of the immunoglobulin heavy chain enhancer. Mol Cancer. 2007;6:23.PubMedPubMedCentral

17.

Ward JM, Ratliff ML, Dozmorov MG, Wiley G, Guthridge JM, Gaffney PM, et al. Expression and methylation data from SLE patient and healthy control blood samples subdivided with respect to ARID3a levels. Data Brief. 2016;9:213–9.PubMedPubMedCentral

18.

Ward JM, Ratliff ML, Dozmorov MG, Wiley G, Guthridge JM, Gaffney PM, et al. Human effector B lymphocytes express ARID3a and secrete interferon alpha. J Autoimmun. 2016;75:130–40.PubMedPubMedCentral

19.

Webb CF, Bryant J, Popowski M, Allred L, Kim D, Harriss J, et al. The ARID family transcription factor bright is required for both hematopoietic stem cell and B lineage development. Mol Cell Biol. 2011;31(5):1041–53.PubMedPubMedCentral

20.

Nixon JC, Ferrell S, Miner C, Oldham AL, Hochgeschwender U, Webb CF. Transgenic mice expressing dominant-negative bright exhibit defects in B1 B cells. J Immunol. 2008;181(10):6913–22.PubMedPubMedCentral

21.

Hayakawa K, Li YS, Shinton SA, Bandi SR, Formica AM, Brill-Dashoff J, et al. Crucial role of increased Arid3a at the pre-B and immature B cell stages for B1a cell generation. Front Immunol. 2019;10:457.PubMedPubMedCentral

22.

Li YS, Zhou Y, Tang L, Shinton SA, Hayakawa K, Hardy RR. A developmental switch between fetal and adult B lymphopoiesis. Ann N Y Acad Sci. 2015;1362:8–15.PubMed

23.

Zhou Y, Li YS, Bandi SR, Tang L, Shinton SA, Hayakawa K, et al. Lin28b promotes fetal B lymphopoiesis through the transcription factor Arid3a. J Exp Med. 2015;212(4):569–80.PubMedPubMedCentral

24.

Simell B, Vuorela A, Ekstrom N, Palmu A, Reunanen A, Meri S, et al. Aging reduces the functionality of anti-pneumococcal antibodies and the killing of Streptococcus pneumoniae by neutrophil phagocytosis. Vaccine. 2011;29(10):1929–34.PubMed

25.

Brooks LRK, Mias GI. Streptococcus pneumoniae’s virulence and host immunity: aging, diagnostics, and prevention. Front Immunol. 2018;9:1366.PubMedPubMedCentral

26.

Oldham AL, Miner CA, Wang HC, Webb CF. The transcription factor bright plays a role in marginal zone B lymphocyte development and autoantibody production. Mol Immunol. 2011;49(1–2):367–79.PubMedPubMedCentral

27.

Baumgarth N. A hard(y) look at B-1 cell development and function. J Immunol. 2017;199(10):3387–94.PubMedPubMedCentral

28.

Sanz I, Wei C, Jenks SA, Cashman KS, Tipton C, Woodruff MC, et al. Challenges and opportunities for consistent classification of human B cell and plasma cell populations. Front Immunol. 2019;10:2458.PubMedPubMedCentral

29.

Ratliff ML, Ward JM, Merrill JT, James JA, Webb CF. Differential expression of the transcription factor ARID3a in lupus patient hematopoietic progenitor cells. J Immunol. 2015;194(3):940–9.PubMed

30.

Ratliff ML, Mishra M, Frank MB, Guthridge JM, Webb CF. The transcription factor ARID3a is important for in vitro differentiation of human hematopoietic progenitors. J Immunol. 2016;196(2):614–23.PubMed

31.

Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A. 2005;102(26):9194–9.PubMedPubMedCentral

32.

Wahlestedt M, Norddahl GL, Sten G, Ugale A, Frisk MA, Mattsson R, et al. An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state. Blood. 2013;121(21):4257–64.PubMed

33.

Zhang WG, Zhu SY, Bai XJ, Zhao DL, Jian SM, Li J, et al. Select aging biomarkers based on telomere length and chronological age to build a biological age equation. Age (Dordr). 2014;36(3):9639.

34.

Lee Y, Sun D, Ori APS, Lu AT, Seeboth A, Harris SE, et al. Epigenome-wide association study of leukocyte telomere length. Aging (Albany NY). 2019;11(16):5876–94.

35.

de Haan G, Lazare SS. Aging of hematopoietic stem cells. Blood. 2018;131(5):479–87.PubMed

36.

van Galen P, Kreso A, Wienholds E, Laurenti E, Eppert K, Lechman ER, et al. Reduced lymphoid lineage priming promotes human hematopoietic stem cell expansion. Cell Stem Cell. 2014;14(1):94–106.PubMed

37.

Camous X, Pera A, Solana R, Larbi A. NK cells in healthy aging and age-associated diseases. J Biomed Biotechnol. 2012;2012:195956.PubMedPubMedCentral

38.

Cichocki F, Grzywacz B, Miller JS. Human NK cell development: one road or many? Front Immunol. 2019;10:2078.PubMedPubMedCentral

39.

Sanz E, Munoz AN, Monserrat J, Van-Den-Rym A, Escoll P, Ranz I, et al. Ordering human CD34+CD10-CD19+ pre/pro-B-cell and CD19- common lymphoid progenitor stages in two pro-B-cell development pathways. Proc Natl Acad Sci U S A. 2010;107(13):5925–30.PubMedPubMedCentral

40.

Dmytrus J, Matthes-Martin S, Pichler H, Worel N, Geyeregger R, Frank N, et al. Multi-color immune-phenotyping of CD34 subsets reveals unexpected differences between various stem cell sources. Bone Marrow Transplant. 2016;51(8):1093–100.PubMed

41.

Montecino-Rodriguez E, Dorshkind K. B-1 B cell development in the fetus and adult. Immunity. 2012;36(1):13–21.PubMedPubMedCentral

42.

Doulatov S, Notta F, Laurenti E, Dick JE. Hematopoiesis: a human perspective. Cell Stem Cell. 2012;10(2):120–36.PubMed

43.

Przemska-Kosicka A, Childs CE, Maidens C, Dong H, Todd S, Gosney MA, et al. Age-related changes in the natural killer cell response to seasonal influenza vaccination are not influenced by a Synbiotic: a randomised controlled trial. Front Immunol. 2018;9:591.PubMedPubMedCentral

44.

Ichii M, Oritani K, Yokota T, Schultz DC, Holter JL, Kanakura Y, et al. Stromal cell-free conditions favorable for human B lymphopoiesis in culture. J Immunol Methods. 2010;359(1–2):47–55.PubMedPubMedCentral

45.

Ichii M, Oritani K, Yokota T, Zhang Q, Garrett KP, Kanakura Y, et al. The density of CD10 corresponds to commitment and progression in the human B lymphoid lineage. PLoS One. 2010;5(9):e12954.PubMedPubMedCentral

46.

Mejia-Ramirez E, Florian MC. Understanding intrinsic hematopoietic stem cell aging. Haematologica. 2020;105(1):22–37.PubMedPubMedCentral

47.

Lepus CM, Gibson TF, Gerber SA, Kawikova I, Szczepanik M, Hossain J, et al. Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/gammac−/−, Balb/c-Rag1−/−gammac−/−, and C.B-17-scid/bg immunodeficient mice. Hum Immunol. 2009;70(10):790–802.PubMedPubMedCentral

48.

Harrison DE, Astle CM. Short- and long-term multilineage repopulating hematopoietic stem cells in late fetal and newborn mice: models for human umbilical cord blood. Blood. 1997;90(1):174–81.PubMed

49.

Holodick NE, Rothstein TL. B cells in the aging immune system: time to consider B-1 cells. Ann N Y Acad Sci. 2015;1362(1):176–87.PubMedPubMedCentral

50.

Cancro MP. Age-associated B Cells. Annu Rev Immunol. 2020;38:315–40.PubMed

51.

Hao Y, O'Neill P, Naradikian MS, Scholz JL, Cancro MP. A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice. Blood. 2011;118(5):1294–304.PubMedPubMedCentral

52.

Rubtsov AV, Rubtsova K, Fischer A, Meehan RT, Gillis JZ, Kappler JW, et al. Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c(+) B-cell population is important for the development of autoimmunity. Blood. 2011;118(5):1305–15.PubMedPubMedCentral

53.

Rundberg Nilsson A, Soneji S, Adolfsson S, Bryder D, Pronk CJ. Human and murine hematopoietic stem cell aging is associated with functional impairments and intrinsic megakaryocytic/Erythroid bias. PLoS One. 2016;11(7):e0158369.PubMedPubMedCentral

54.

Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science (New York, NY). 2011;333(6039):218–21.

55.

Nixon JC, Rajaiya JB, Ayers N, Evetts S, Webb CF. The transcription factor, bright, is not expressed in all human B lymphocyte subpopulations. Cell Immunol. 2004;228(1):42–53.PubMed

56.

Tomellini E, Fares I, Lehnertz B, Chagraoui J, Mayotte N, MacRae T, et al. Integrin-alpha3 Is a Functional Marker of Ex Vivo Expanded Human Long-Term Hematopoietic Stem Cells. Cell Rep. 2019;28(4):1063–73.e5.PubMed

Title: ARID3a expression in human hematopoietic stem cells is associated with distinct gene patterns in aged individuals
Authors: Michelle L. Ratliff
Joshua Garton
Judith A. James
Carol F. Webb
Publication date: 01-12-2020
Publisher: BioMed Central
Published in: Immunity & Ageing / Issue 1/2020
Electronic ISSN: 1742-4933
DOI: https://doi.org/10.1186/s12979-020-00198-6

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2020

COVID-19: age, Interleukin-6, C-reactive protein, and lymphocytes as key clues from a multicentre retrospective study

A very low thymus function identifies patients with substantial increased risk for long-term mortality after kidney transplantation

Immune cell extracellular vesicles and their mitochondrial content decline with ageing

The correlation between the Th17/Treg cell balance and bone health

Age-related changes in T lymphocytes of patients with head and neck squamous cell carcinoma

Can an effective SARS-CoV-2 vaccine be developed for the older population?

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials