scholarly journals Cyclophilin A regulates protein phase separation and mitigates haematopoietic stem cell aging

2021 ◽  
Author(s):  
Laure Maneix ◽  
Polina Iakova ◽  
Shannon E. Moree ◽  
Jordon C.K. King ◽  
David B. Sykes ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Phase Separation ◽  
Cyclophilin A ◽  
Haematopoietic Stem Cell ◽  
Cell Aging ◽  
Haematopoietic Stem Cells ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Stem Cell Aging

AbstractLoss of protein quality is a driving force of aging1. The accumulation of misfolded proteins represents a vulnerability for long-lived cells, such as haematopoietic stem cells. How these cells, which have the ability to reconstitute all haematopoietic lineages throughout life2, maintain their regenerative potential and avert the effects of aging is poorly understood. Here, we determined the protein content in haematopoietic stem and progenitor cells to identify prevalent chaperones that support proteome integrity. We identified Peptidyl-Prolyl Isomerase A (PPIA or Cyclophilin A) as the dominant cytosolic foldase in this cell population. Loss of PPIA accelerated aging in the mouse stem cell compartment. In an effort to define targets of PPIA, we found that RNA- and DNA-binding proteins are common substrates of this chaperone. These proteins are enriched in intrinsically disordered regions (IDRs), which can catalyse protein condensation3. Isomerized target prolines are almost exclusively located within IDRs. We discovered that over 20% of PPIA client proteins are known to participate in liquid-liquid phase separation, enabling the formation of supramolecular membrane-less organelles. Using the poly-A binding protein PABPC1 as an example, we demonstrate that PPIA promotes phase separation of ribonucleoprotein particles, thereby increasing cellular stress resistance. Haematopoietic stem cell aging is associated with a decreased expression of PPIA and reduced synthesis of intrinsically disordered proteins. Our findings link the ubiquitously expressed chaperone PPIA to phase transition and identify macromolecular condensation as a potential determinant of the aging process in haematopoietic stem cells.

scholarly journals Protein Phase Separation in Hematopoietic Stem Cell Aging

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5003-5003
Author(s):  
Laure Maneix ◽  
Polina Iakova ◽  
Shannon Moree ◽  
Melanie Sweeney ◽  
Nagaishwarya Moka ◽  
...  
Keyword(s):  
Phase Transition ◽  
Stem Cell ◽  
Phase Separation ◽  
Research Funding ◽  
Protein Translation ◽  
Disordered Proteins ◽  
Cell Aging ◽  
Hematopoietic Stem ◽  
Intrinsically Disordered ◽  
Stem Cell Aging

Imbalanced protein homeostasis (proteostasis) is a driver of aging and a vulnerability for long-lived cells such as hematopoietic stem cells. To determine critical proteostasis factors, we analyzed the proteome of hematopoietic stem and progenitor cells and found prolyl isomerases to be the dominant cytosolic chaperones. Genetic removal of prolyl isomerases led to accelerated aging in the stem cell compartment. We identified intrinsically disordered proteins as common substrates of these chaperones, including several key players that control phase transition. Phase separation allows the formation of supramolecular membrane-less organelles that regulate DNA and RNA biology as well as protein translation. Using microscopy and biochemistry, we show that prolyl isomerases promote phase separation and thereby increase cellular resistance to stress. Our research links a ubiquitously expressed chaperone family to phase transition and identifies macromolecular condensation dynamics as a driver of blood stem cell aging. Disclosures Yellapragada: Novartis: Employment, Other: Spouse Employment ; Celgene: Research Funding; BMS: Research Funding; Takeda: Research Funding.

scholarly journals Single Cell Phenotyping Reveals Heterogeneity among Haematopoietic Stem Cells Following Infection

2016 ◽  
Author(s):  
Adam L MacLean ◽  
Maia A Smith ◽  
Juliane Liepe ◽  
Aaron Sim ◽  
Reema Khorshed ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Single Cell ◽  
Life History Theory ◽  
Cell Function ◽  
Trichinella Spiralis ◽  
Haematopoietic Stem Cell ◽  
Haematopoietic Stem Cells ◽  
Hsc Niche

AbstractThe haematopoietic stem cell (HSC) niche provides essential micro-environmental cues for the production and maintenance of HSCs within the bone marrow. During inflammation, haematopoietic dynamics are perturbed, but it is not known whether changes to the HSC-niche interaction occur as a result. We visualise HSCs directly in vivo, enabling detailed analysis of the 3D niche dynamics and migration patterns in murine bone marrow following Trichinella spiralis infection. Spatial statistical analysis of these HSC trajectories reveals two distinct modes of HSC behaviour: (i) a pattern of revisiting previously explored space, and (ii) a pattern of exploring new space. Whereas HSCs from control donors predominantly follow pattern (i), those from infected mice adopt both strategies. Using detailed computational analyses of cell migration tracks and life-history theory, we show that the increased motility of HSCs following infection can, perhaps counterintuitively, enable mice to cope better in deteriorating HSC-niche micro-environments following infection.Author SummaryHaematopoietic stem cells reside in the bone marrow where they are crucially maintained by an incompletely-determined set of niche factors. Recently it has been shown that chronic infection profoundly affects haematopoiesis by exhausting stem cell function, but these changes have not yet been resolved at the single cell level. Here we show that the stem cell–niche interactions triggered by infection are heterogeneous whereby cells exhibit different behavioural patterns: for some, movement is highly restricted, while others explore much larger regions of space over time. Overall, cells from infected mice display higher levels of persistence. This can be thought of as a search strategy: during infection the signals passed between stem cells and the niche may be blocked or inhibited. Resultantly, stem cells must choose to either ‘cling on’, or to leave in search of a better environment. The heterogeneity that these cells display has immediate consequences for translational therapies involving bone marrow transplant, and the effects that infection might have on these procedures.

Serine Metabolism Controls Dental Pulp Stem Cell Aging by Regulating the DNA Methylation of p16

2020 ◽  
Vol 100 (1) ◽  
pp. 90-97
Author(s):  
R.L. Yang ◽  
H.M. Huang ◽  
C.S. Han ◽  
S.J. Cui ◽  
Y.K. Zhou ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Stem Cell ◽  
Dental Pulp ◽  
Permanent Teeth ◽  
Deciduous Teeth ◽  
Cell Aging ◽  
Differentiation Capacity ◽  
Stem Cell Aging ◽  
Serine Metabolism

To investigate the characteristics and molecular events of dental pulp stem cells (DPSCs) for tissue regeneration with aging, we isolated and analyzed the stem cells from human exfoliated deciduous teeth (SHED) and permanent teeth of young (Y-DPSCs) and old (A-DPSCs) adults. Results showed that the stemness and osteogenic differentiation capacity of DPSCs decreased with aging. The RNA sequencing results showed that glycine, serine, and threonine metabolism was one of the most enriched gene clusters among SHED, Y-DPSCs, and A-DPSCs, according to analysis based on the Kyoto Encyclopedia of Genes and Genomes. The expression of serine metabolism–related enzymes phosphoserine aminotransferase 1 (PSAT1) and phosphoglycerate (PHGDH) decreased in A-DPSCs and provided less methyl donor S-adenosylmethionine (SAM) for DNA methylation, leading to the hypomethylation of the senescence marker p16 (CDNK2A). Furthermore, the proliferation and differentiation capacity of Y-DPSCs and SHED decreased after PHGDH siRNA treatment, which reduced the level of SAM. Convincingly, the ratios of PSAT1-, PHGDH-, or proliferating cell nuclear antigen–positive cells in the dental pulp of old permanent teeth were less than those in the dental pulp of deciduous teeth and young permanent teeth. In summary, the stemness and differentiation capacity of DPSCs decreased with aging. The decreased serine metabolism in A-DPSCs upregulated the expression of p16 via attenuating its DNA methylation, resulting in DPSC aging. Our finding indicated that serine metabolism and 1 carbon unit participated in stem cell aging, which provided new direction for stem cell aging study and intervention.

Caloric restriction maintains stem cells through niche and regulates stem cell aging

2019 ◽  
Vol 98 (1) ◽  
pp. 25-37 ◽  
Author(s):  
Nagarajan Maharajan ◽  
Karthikeyan Vijayakumar ◽  
Chul Ho Jang ◽  
Goang-Won Cho
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Caloric Restriction ◽  
Cell Aging ◽  
Stem Cell Aging

scholarly journals Investigation of Stem Cell Aging Throughout the Lifetime and Therapeutic Opportunities

2020 ◽  
Author(s):  
Sarah Karimi ◽  
Setareh Raoufi ◽  
Zohreh Bagher
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Aging Process ◽  
Cell Function ◽  
Cell Activity ◽  
The Body ◽  
Natural Phenomenon ◽  
Cell Aging ◽  
Molecular Pathways ◽  
Stem Cell Aging

Introduction: Aging is a natural phenomenon that is caused by changes in the cells of the body. Theoretically, aging starts from birth and lasts throughout life. These changes affect the function of the cells. Also, in old tissues, the capacity for homeostasis and tissue repair is decline due to destructive changes in specific tissue stem cells, niche of stem cells and systemic factors that regulate stem cell activity. Understanding molecular pathways that disrupt stem cell function during aging is crucial for the development of new treatments for aging-associated diseases. In this article, the symptoms of stem cell aging and the key molecular pathways that are commonly used for the aging of stem cells were discussed. We will consider experimental evidence for all of the mechanisms and evaluate the way that can slow down or even stop the aging process. Finally, we will look at the aging process of three types of stem cells.

scholarly journals Klotho Deficiency Accelerates Stem Cells Aging by Impairing Telomerase Activity

2018 ◽  
Vol 74 (9) ◽  
pp. 1396-1407 ◽  
Author(s):  
Mujib Ullah ◽  
Zhongjie Sun
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Critical Role ◽  
Telomerase Activity ◽  
Cell Aging ◽  
Treated Animal ◽  
Differentiation Potential ◽  
Telomere Shortening ◽  
Altered Expression ◽  
Stem Cell Aging

Abstract Understanding the effect of molecular pathways involved in the age-dependent deterioration of stem cell function is critical for developing new therapies. The overexpression of Klotho (KL), an antiaging protein, causes treated animal models to enjoy extended life spans. Now, the question stands: Does KL deficiency accelerate stem cell aging and telomere shortening? If so, what are the specific mechanisms by which it does this, and is cycloastragenol (CAG) treatment enough to restore telomerase activity in aged stem cells? We found that KL deficiency diminished telomerase activity by altering the expression of TERF1 and TERT, causing impaired differentiation potential, pluripotency, cellular senescence, and apoptosis in stem cells. Telomerase activity decreased with KL-siRNA knockdown. This suggests that both KL and telomeres regulate the stem cell aging process through telomerase subunits TERF1, POT1, and TERT using the TGFβ, Insulin, and Wnt signaling. These pathways can rejuvenate stem cell populations in a CD90-dependent mechanism. Stem cell dysfunctions were largely provoked by KL deficiency and telomere shortening, owing to altered expression of TERF1, TGFβ1, CD90, POT1, TERT, and basic fibroblast growth factor (bFGF). The CAG treatment partially rescued telomerase deterioration, suggesting that KL plays a critical role in life-extension by regulating telomere length and telomerase activity.

scholarly journals Manifestations and mechanisms of stem cell aging

2011 ◽  
Vol 193 (2) ◽  
pp. 257-266 ◽  
Author(s):  
Ling Liu ◽  
Thomas A. Rando
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Adult Stem Cells ◽  
Cell Aging ◽  
Functional Changes ◽  
Cell Based Therapy ◽  
Age Related ◽  
Stem Cell Aging ◽  
Genetic Interventions ◽  
Cell Functionality

Adult stem cells exist in most mammalian organs and tissues and are indispensable for normal tissue homeostasis and repair. In most tissues, there is an age-related decline in stem cell functionality but not a depletion of stem cells. Such functional changes reflect deleterious effects of age on the genome, epigenome, and proteome, some of which arise cell autonomously and others of which are imposed by an age-related change in the local milieu or systemic environment. Notably, some of the changes, particularly epigenomic and proteomic, are potentially reversible, and both environmental and genetic interventions can result in the rejuvenation of aged stem cells. Such findings have profound implications for the stem cell–based therapy of age-related diseases.

The Use of Plerixafor for Peripheral Blood Stem Cell Mobilisation Reduces the Frequency of Mobilisation Failure in Patients Planned to Undergo Autologous Transplantation

2010 ◽  
Vol 00 (04) ◽  
pp. 24 ◽  
Author(s):  
Dag Josefsen ◽  
Catherine Rechnitzer ◽  
Katriina Parto ◽  
Gunnar Kvalheim ◽  
◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Peripheral Blood ◽  
Autologous Transplantation ◽  
Case Series ◽  
High Dose Chemotherapy ◽  
Haematopoietic Stem Cell ◽  
High Dose ◽  
Haematopoietic Stem Cells ◽  
Stem Cell Mobilisation

High-dose chemotherapy with or without radiation followed by autologous haematopoietic stem cell transplantation (auto-HSCT) is now the standard of care for patients with chemosensitive relapsed aggressive non-Hodgkin’s lymphoma (NHL), chemosensitive relapsed Hodgkin’s disease (HD) and multiple myeloma (MM). Autologous haematopoietic stem cells also provide haematopoietic support after the administration of high-dose chemotherapy in relapsed NHL and MM. However, certain patients fail to mobilise a sufficient number of haematopoietic stem cells using standard cytokine-assisted mobilisation strategies. Recently, plerixafor, a novel bicyclam capable of specifically and reversibly binding to the CXCR4 receptor on haematopoietic stem cells, has been granted European approval, in combination with granulocyte colony-stimulating factor, for the enhancement of haematopoietic stem cell mobilisation to the peripheral blood for collection and subsequent autotransplantation in poorly mobilising lymphoma and MM patients. In this article the authors present their initial experience with plerixafor in a case series at their own institutions in Scandinavia.

Stem Cell Senescence: the Obstacle of the Treatment of Degenerative Disk Disease

2019 ◽  
Vol 14 (8) ◽  
pp. 654-668 ◽  
Author(s):  
Ying Chen ◽  
Liling Tang
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Senescence ◽  
Cell Aging ◽  
Limiting Factor ◽  
Low Back ◽  
The Family ◽  
Stem Cell Aging ◽  
Negative Effect ◽  
Ivd Degeneration

Intervertebral disc (IVD) has a pivotal role in the maintenance of flexible motion. IVD degeneration is one of the primary causes of low back pain and disability, which seriously influences patients’ health, and increases the family and social economic burden. Recently, stem cell therapy has been proven to be more effective on IVD degeneration disease. However, stem cell senescence is the limiting factor in the IVD degeneration treatment. Senescent stem cells have a negative effect on the self-repair on IVD degeneration. In this review, we delineate that the factors such as telomerase shortening, DNA damage, oxidative stress, microenvironment and exosomes will induce stem cell aging. Recent studies tried to delay the aging of stem cells by regulating the expression of aging-related genes and proteins, changing the activity of telomerase, improving the survival microenvironment of stem cells and drug treatment. Understanding the mechanism of stem cell aging and exploring new approaches to delay or reverse stem cell aging asks for research on the repair of the degenerated disc.

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