Biomedical subjects

Peter M Lansdorp

Publications and source records attributed to Peter M Lansdorp.

42 records · Page 3Linked to original sources

PubMed2002

Longitudinal studies of telomere length in feline blood cells: implications for hematopoietic stem cell turnover in vivo.

OBJECTIVE: To address questions about stem cell turnover in relation to telomere length dynamics, we analyzed telomere length in serial blood samples from cats. MATERIALS AND METHODS: Lymphocytes and granulocytes from two newborn kittens, a 2-year-old cat, a 10-year-old recipient of a double autologous stem cell transplant, and a 10-year-old control animal were analyzed by fluorescence in situ hybridization and flow cytometry at 2-week intervals over a 1-year period. RESULTS: At study onset, long telomeres were found in granulocytes and lymphocytes from the two kittens (mean +/- SD: 70.2 +/- 3.1 and 72.5 +/- 3.1 telomere fluorescence units [TFU], respectively) compared with the 2-year-old cat (55.6 +/- 2.5 and 64.1 +/- 4.3 TFU, respectively) and the two adult animals (49.6 +/- 1.5 and 45.4 +/- 0.8 TFU, respectively). The rate of telomere shortening in both granulocytes and lymphocytes was most rapid in the kittens (slope: -16.7 +/- 1.4 and -15.6 +/- 0.2 TFU/year, respectively). As in humans, telomere shortening with age was more rapid in lymphocytes than in granulocytes. An average rate of telomere attrition of -0.52 +/- 0.03 TFU per cell division was calculated for cultured lymphocytes from the two kittens, approximately 5-fold higher than the rate observed in human cells. CONCLUSIONS: The average telomere length in cats is 5- to 10-fold longer than in humans, but the rate of telomere shortening is much higher both in vivo and in vitro. These observations are compatible with similar stem cell kinetics in both species.

Aging↗

PubMed2002

Telomere maintenance in human B lymphocytes.

Telomere shortening has been causally linked to replicative senescence in human cells. To characterize telomere-length heterogeneity in peripheral blood cells of normal individuals, we analysed the mean length of telomeric repeat sequences in subpopulations of peripheral blood leucocytes, using fluorescence in situ hybridization and flow cytometry (flow-FISH). Although the telomere length of most haematopoietic subsets was within the same range, the mean telomere length was found to be 15% higher in B compared with T lymphocytes in adult peripheral blood. Whereas telomere loss with ageing corresponded to 33 base pairs (bp) per year in T cells, telomere shortening was slower in B cells, corresponding to 15 bp per year. Separation of adult B-lymphocyte subpopulations based on CD27 expression revealed that telomere length was almost 2 kb longer in CD19+CD27+ (memory) compared with CD19+CD27- (naive) cells. Furthermore, peripheral blood B cells were activated in vitro. Whereas B-cell activation with Staphylococcus aureus Cowan strain (SAC) did not increase telomere length, a striking telomere elongation was observed when cells were stimulated with SAC and interleukin 2 to induce plasma cell differentiation. Our observations support the concept that telomere dynamics in B cells are distinct from other haematopoietic cell lineages and that telomere elongation may play an essential role in the generation of long-term B memory cells.

Adolescent↗

PubMed2002

Telomere shortening in hematopoietic stem cell transplantation: a potential mechanism for late graft failure?

Telomeres serve to maintain the structural integrity of chromosomes, yet each somatic cell division is associated with a decrease in telomere length. The cumulative decrease in telomere length can impose an upper limit for the number of cell divisions that can occur before a cell senesces. When studied in vitro with fibroblasts, this limit is referred to as the Hayflick limit and usually occurs after 40 to 80 cell doublings. In theory, a similar replicative potential in a hematopoietic stem cell could support hematopoiesis in a person for more than 100 years. However, stem cells differentiate, and the telomere length differs among chromosomes within a single cell, among cell types, and among age-matched individuals. This variation in telomere length raises the possibility that long-term hematopoiesis by transplanted stem cells could, depending on the telomere length of the engrafted stem cell and the proliferative demand to which it is subjected, reach a Hayflick limit during the life span of the patient. Although significant shortening of telomeres is reported to occur within the first year posttransplantation, as yet no evidence has indicated that this shortening is associated with marrow function. In this review, we summarize reports on telomere shortening in stem cell transplantation recipients and report 2 cases in which graft failure is associated with significant telomere shortening.

Adolescent↗

PubMed2002

Feature analysis and centromere segmentation of human chromosome images using an iterative fuzzy algorithm.

Classification of homologous chromosomes is essential to advanced studies of cancer genetics. Centromere intensities are believed to be an important differentiating feature between homologs. Therefore, segmentation of centromeres is a major step toward the realization of homolog classification. This paper describes an iterative fuzzy algorithm which successfully segments centromeres from images of human chromosomes prepared using fluorescence in-situ hybridization technique. The algorithm is based on assigning a fuzzy membership value to each pixel in the centromere image. An iterative algorithm then updates and minimizes a defined error function. Chromosome 22, a highly heteromorphic chromosome, is used to verify the centromere segmentation method. Homologs of this chromosome are classified based on their segmented centromere intensities as well as their morphological differences. The classification results of these two methods agree completely and are used to validate our developed algorithm.

Algorithms↗

PubMed2002

Stem cells: hype and reality.

This update discusses what is known regarding embryonic and adult tissue-derived pluripotent stem cells, including the mechanisms underlying self-renewal without senescence, differentiation in multiple cell types both in vitro and in vivo, and future potential clinical uses of such stem cells. In Section I, Dr. Lansdorp reviews the structure and function of telomerase, the enzyme that restores telomeric ends of chromosomes upon cell division, highly present in embryonic stem cells but not adult stem cells. He discusses the structure and function of telomerase and signaling pathways activated by the enzyme, with special emphasis on normal and leukemic hematopoietic stem cells. In Section II, Dr. Pera reviews the present understanding of mammalian pluripotent embryonic stem cells. He discusses the concept of pluripotentiality in its embryonic context, derivation of stem cells from embryonic or fetal tissue, the basic properties of the stem cells, and methods to produce specific types of differentiated cell from stem cells. He examines the potential applications of stem cells in research and medicine and some of the barriers that must be crossed to achieve these goals. In Section III, Dr. Verfaillie reviews the present understanding of pluripotency of adult stem cells. She discusses the concept of stem cell plasticity, a term used to describe the greater potency described by several investigators of adult tissue-derived stem cells, critically reviews the published studies demonstrating stem cell plasticity, and possible mechanisms underlying such plasticity, and examines the possible role of pluripotent adult stem cells in research and medicine.

Animals↗

PubMedDate not supplied

Telomeres, telomerase, and hematopoietic stem cell biology.

Telomeres are composed of the tandem DNA repeats and associated proteins that cap the end of linear chromosomes. They provide stability to the chromosome and protect against DNA loss associated with cellular replication. Telomeres are maintained by the reverse transcriptase, telomerase. The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation. Hematopoietic stem cells have an impressive but finite proliferative potential and demonstrate telomeric shortening during replicative aging despite expression of low levels of telomerase. Recently, the important role of telomeres in human illness has been highlighted by studies of the rare genetic disorder dyskeratosis congenita. Here we review the role of telomeres and telomerase in the function and regulation of the hematopoietic stem cell compartment and their importance in hematologic disease.

Cell Lineage↗