Telomere length and proliferation potential of hematopoietic stem cells

Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
Journal of Cell Science (Impact Factor: 5.43). 02/1995; 108 ( Pt 1)(1):1-6.
Source: PubMed


Hematopoietic stem cells have typically been defined as pluripotent cells with self-renewal capacity. Recent studies have shown striking differences in the mean length of telomeric repeat sequences at the end of chromosomes from human hematopoietic cells at different stages of development. The most likely explanation for these observations is that hematopoietic stem cells, like all other somatic cells studied to date, lose telomeric DNA upon each cell division. In this review, limitations in the replicative potential of hematopoietic stem cells are discussed in the context of possible clinical use of such cells for transplantation and gene therapy.

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    • "Evidence for the loss of telomeric DNA with proliferation of HSCs and ageing exists for more than two decades (Vaziri et al., 1994). For HSCs to be efficient in maintaining lifelong homeostasis, it was proposed that there might be a small sub-set of HSCs that remains quiescent or expresses telomerase at high levels (Lansdorp, 1995). Evidence suggests that both of the hypotheses might be working simultaneously for HSCs to possess LT-proliferation potential. "
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    ABSTRACT: In most of the mammalian tissues, homeostasis as well as injury repair depends upon a small number of resident adult stem cells. The decline in tissue/organ function in aged organisms has been directly linked with poorly functioning stem cells. Altered function of hematopoietic stem cells (HSCs) is at the center of an ageing hematopoietic system, a tissue with high cellular turnover. Poorly engrafting, myeloid biased HSCs with higher levels of DNA damage accumulation are the hallmark features of an aged hematopoietic system. These cells show higher proliferation rate than their younger counterparts. It was proposed that quiescence of these cells over long period of time leads to accumulation of DNA damage, eventually resulting in poor function/pathological conditions in hematopoietic system. However, various mouse models with pre-mature ageing phenotype also show highly proliferative HSCs. This review examines the evidence that links proliferation of HSCs with ageing, which leads to functional changes in the hematopoietic system. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jan 2016 · Developmental Dynamics
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    • "During DNA replication, the linear ends of chromosomes are eroded at each cell division due to the end replication problem.1 Telomeres, the very ends of linear chromosomes, are predominantly composed of tandem repeats of short sequences; in vertebrates, the repeats consist of the TTAGGG hexanucleotide.2 Telomere lengths are also remarkably heterogeneous among individuals and vary according to the origin, age, and proliferative history of cells.3,4 Telomere length variations among individuals of the same age are, therefore, thought to be related to variations in ageing and longevity.5 "
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    ABSTRACT: Telomerase reverse transcriptase (TERT) is the protein component of telomerase and combined with an RNA molecule, telomerase RNA component, forms the telomerase enzyme responsible for telomere elongation. Telomerase is essential for maintaining telomere length from replicative attrition and thus contributes to the preservation of genome integrity. Although diverse mouse models have been developed and studied to prove the physiological roles of telomerase as a telomere- elongating enzyme, recent studies have revealed non-canonical TERT activities beyond telomeres. To gain insights into the physiological impact of extra-telomeric roles, this review revisits the strategies and phenotypes of telomerase mouse models in terms of the extra-telomeric functions of telomerase.
    Full-text · Article · Jan 2014 · Yonsei medical journal
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    • ") were seeded in triplicate in 96-well plates (Nalgene Nunc) and cultured in serum depleted media containing various growth factors. The serum-deprived media is a modification of the serum-deprived media developed for growth of haematopoietic progenitors (Migliaccio et al., 1988; Lansdorp, 1995) and adapted for the growth of stromal progenitors (Gronthos and Simmons, 1995). Cells were incubated for 5 days with the following growth factors at 10–100 ng/ml: recombinant human BMP-2 (Cytolab/Peprotech, Rehovot, Israel), BMP-7 (Stryker Biotech, St Leonards, NSW, Australia), recombinant human EGF (Peprotech, Rocky Hill, NJ) recombinant human IGF-1 (Gropep, Thebarton, SA, Australia), recombinant human FGF-2 (Cytolab/Peprotech), recombinant human PDGF-BB (Peprotech), recombinant human TGF-b1 (Cytolab/Peprotech), recombinant human TGF-b3 (Cytolab/Peprotech), recombinant human TGF-a (Peprotech). "
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    ABSTRACT: Since discovery, significant interest has been generated in the potential application of mesenchymal stem cells or multipotential stromal cells (MSC) for tissue regeneration and repair, due to their proliferative and multipotential capabilities. Although the sheep is often used as a large animal model for translating potential therapies for musculoskeletal injury and repair, the characteristics of MSC from ovine bone marrow have been inadequately described. Histological and gene expression studies have previously shown that ovine MSC share similar properties with human and rodents MSC, including their capacity for clonogenic growth and multiple stromal lineage differentiation. In the present study, ovine bone marrow derived MSCs positively express cell surface markers associated with MSC such as CD29, CD44 and CD166, and lacked expression of CD14, CD31 and CD45. Under serum-deprived conditions, proliferation of MSC occurred in response to EGF, PDGF, FGF-2, IGF-1 and most significantly TGF-alpha. While subcutaneous transplantation of ovine MSC in association with a ceramic HA/TCP carrier into immunocomprimised mice resulted in ectopic osteogenesis, adipogenesis and haematopoietic-support activity, transplantation of these cells within a gelatin sponge displayed partial chondrogenesis. The comprehensive characterisation of ovine MSC described herein provides important information for future translational studies involving ovine MSC.
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