bims-minfam 2021-06-20 papers

Issue of 2021–06–20
seven papers selected by
Ayesh Seneviratne, University of Toronto

J Exp Med. 2021 Jul 05. pii: e20201544. [Epub ahead of print]218(7):

Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS.

Jennifer J Trowbridge, Daniel T Starczynowski.

With a growing aged population, there is an imminent need to develop new therapeutic strategies to ameliorate disorders of hematopoietic aging, including clonal hematopoiesis and myelodysplastic syndrome (MDS). Cell-intrinsic dysregulation of innate immune- and inflammatory-related pathways as well as systemic inflammation have been implicated in hematopoietic defects associated with aging, clonal hematopoiesis, and MDS. Here, we review and discuss the role of dysregulated innate immune and inflammatory signaling that contribute to the competitive advantage and clonal dominance of preleukemic and MDS-derived hematopoietic cells. We also propose how emerging concepts will further reveal critical biology and novel therapeutic opportunities.

DOI: https://doi.org/10.1084/jem.20201544

J Exp Med. 2021 Jul 05. pii: e20201541. [Epub ahead of print]218(7):

Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection.

Francisco Caiado, Eric M Pietras, Markus G Manz.

Inflammation is an evolutionarily selected defense response to infection or tissue damage that involves activation and consumption of immune cells in order to reestablish and maintain organismal integrity. In this process, hematopoietic stem cells (HSCs) are themselves exposed to inflammatory cues and via proliferation and differentiation, replace mature immune cells in a demand-adapted fashion. Here, we review how major sources of systemic inflammation act on and subsequently shape HSC fate and function. We highlight how lifelong inflammatory exposure contributes to HSC inflamm-aging and selection of premalignant HSC clones. Finally, we explore emerging areas of interest and open questions remaining in the field.

DOI: https://doi.org/10.1084/jem.20201541

J Vis Exp. 2021 May 26.

Bone Marrow Transplantation Procedures in Mice to Study Clonal Hematopoiesis.

Eunbee Park, Megan A Evans, Heather Doviak, Keita Horitani, Hayato Ogawa, Yoshimitsu Yura, Ying Wang, Soichi Sano, Kenneth Walsh.

Clonal hematopoiesis is a prevalent age-associated condition that results from the accumulation of somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Mutations in driver genes, that confer cellular fitness, can lead to the development of expanding HSPC clones that increasingly give rise to progeny leukocytes harboring the somatic mutation. Because clonal hematopoiesis has been associated with heart disease, stroke, and mortality, the development of experimental systems that model these processes is key to understanding the mechanisms that underly this new risk factor. Bone marrow transplantation procedures involving myeloablative conditioning in mice, such as total-body irradiation (TBI), are commonly employed to study the role of immune cells in cardiovascular diseases. However, simultaneous damage to the bone marrow niche and other sites of interest, such as the heart and brain, is unavoidable with these procedures. Thus, our lab has developed two alternative methods to minimize or avoid possible side effects caused by TBI: 1) bone marrow transplantation with irradiation shielding and 2) adoptive BMT to non-conditioned mice. In shielded organs, the local environment is preserved allowing for the analysis of clonal hematopoiesis while the function of resident immune cells is unperturbed. In contrast, the adoptive BMT to non-conditioned mice has the additional advantage that both the local environments of the organs and the hematopoietic niche are preserved. Here, we compare three different hematopoietic cell reconstitution approaches and discuss their strengths and limitations for studies of clonal hematopoiesis in cardiovascular disease.

DOI: https://doi.org/10.3791/61875

Exp Anim. 2021 ;70(Supplement): S40-S42

Aging.

DOI: https://doi.org/10.1538/expanim.70suppl-G4

Blood. 2021 Jun 17. pii: blood.2020010163. [Epub ahead of print]

CHIP & HIPs: Clonal Hematopoiesis is Common in Hip Arthroplasty Patients and Associates with Autoimmune Disease.

Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of 'healthy' hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variants with allele frequencies [VAF] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF 1-2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%) and ASXL1 (3.5%). CHIP significantly associated with lower hemoglobin, higher mean corpuscular volume, prior/present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AID; multivariate adjusted odds ratio, 6.6; 95% confidence interval [1.7, 30]; p=0.0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for management of patients with OA and AID or mild anemia, and question use of hip bone-derived cells as 'healthy' experimental controls.

DOI: https://doi.org/10.1182/blood.2020010163

Ageing Res Rev. 2021 Jun 14. pii: S1568-1637(21)00140-9. [Epub ahead of print] 101393

Fibroageing: An ageing pathological feature driven by dysregulated extracellular matrix-cell mechanobiology.

Moisés Selman, Annie Pardo.

Ageing is a multifactorial biological process leading to a progressive decline of physiological functions. The process of ageing includes numerous changes in the cells and the interactions between cell-cell and cell-microenvironment remaining as a critical risk factor for the development of chronic degenerative diseases. Systemic inflammation, known as inflammageing, increases as a consequence of ageing contributing to age-related morbidities. But also, persistent and uncontrolled activation of fibrotic pathways, with excessive accumulation of extracellular matrix (ECM) and organ dysfunction is markedly more frequent in the elderly. In this context, we introduce here the concept of Fibroageing, that is, the propensity to develop tissue fibrosis associated with ageing, and propose that ECM is a key player underlying this process. During ageing, molecules of the ECM become damaged through many modifications including glycation, crosslinking, and accumulation, leading to matrix stiffness which intensifies ageing-associated alterations. We provide a framework with some mechanistic hypotheses proposing that stiff ECM, in addition to the well-known activation of fibrotic positive feedback loops, affect several of the hallmarks of ageing, such as cell senescence and mitochondrial dysfunction, and in this context, is a key mechanism and a driver thread of Fibroageing.

Keywords: Ageing; extracellular matrix; fibrosis; senescence

DOI: https://doi.org/10.1016/j.arr.2021.101393

Front Physiol. 2021 ;12 674013

Proteomics and Epidemiological Models of Human Aging.

Ceereena Ubaida-Mohien, Ruin Moaddel, Ann Zenobia Moore, Pei-Lun Kuo, Faraz Faghri, Ravi Tharakan, Toshiko Tanaka, Mike A Nalls, Luigi Ferrucci.

Human aging is associated with a decline of physical and cognitive function and high susceptibility to chronic diseases, which is influenced by genetics, epigenetics, environmental, and socio-economic status. In order to identify the factors that modulate the aging process, established measures of aging mechanisms are required, that are both robust and feasible in humans. It is also necessary to connect these measures to the phenotypes of aging and their functional consequences. In this review, we focus on how this has been addressed from an epidemiologic perspective using proteomics. The key aspects of epidemiological models of aging can be incorporated into proteomics and other omics which can provide critical detailed information on the molecular and biological processes that change with age, thus unveiling underlying mechanisms that drive multiple chronic conditions and frailty, and ideally facilitating the identification of new effective approaches for prevention and treatment.

Keywords: aging models; biological pathways; epidemiological models; longitudinal cross-sectional; machine learning and artificial intelligence; phenotypes; proteomics; resilience

DOI: https://doi.org/10.3389/fphys.2021.674013