Bone Marrow-Derived Cells: The Influence of Aging and Cellular Senescence

Abstract

During the course of an entire lifespan, tissue repair and regeneration is made possible by the presence of adult stem cells. Stem cell expansion, maintenance, and differentiation must be tightly controlled to assure longevity. Hematopoietic stem cells (HSC) are greatly solicited given the daily high blood cell turnover. Moreover, several bone marrow-derived cells including HSC, mesenchymal stromal cells (MSC), and endothelial progenitor cells (EPC) also significantly contribute to peripheral tissue repair and regeneration, including tumor formation. Therefore, factors influencing bone marrow-derived cell proliferation and functions are likely to have a broad impact. Aging has been identified as one of these factors. One hypothesis is that aging directly affects stem cells as a consequence of exhaustive proliferation. Alternatively, it is also possible that aging indirectly affects stem cells by acting on their microenvironment. Cellular senescence is believed to have evolved as a tumor suppressor mechanism capable of arresting growth to reduce risk of malignancy. In opposition to apoptosis, senescent cells accumulate in tissues. Recent evidence suggests their accumulation contributes to the phenotype of aging. Senescence can be activated by both telomere-dependent and telomere-independent pathways. Genetic alteration, genome-wide DNA damage, and oxidative stress are inducers of senescence and have recently been identified as occurring in bone marrow-derived cells. Below is a review of the link between cellular senescence, aging, and bone marrow-derived cells, and the possible consequences aging may have on bone marrow trans plantation procedures and emerging marrow-derived cell-based therapies.

Binding to WGR Domain by Salidroside Activates PARP1 and Protects Hematopoietic Stem Cells from Oxidative Stress

“…These findings not only provide a molecular explanation for Salidroside-stimulated PARP1 activation in HSC maintenance under oxidative stress, but also suggest new targets for therapeutically exploring the pathogenic role of oxidative stress in hematologic diseases. oxidative stress responses, including Atm, Fancc, Fancd2, FoxO, and in DNA damage repair, including Lig4, Dna-pk, Ku80, Xpd, mTR, show elevated ROS levels and sustained DNA damage accumulation leading to premature HSC exhaustion (2,4,5,18,19,24,26,28,31,33,34,41,47).…”

Expression profile of genes identified in human spermatogonial stem cell‐like cells using suppression subtractive hybridization

“…Because of what is known as the Hayflick limit [Hayflick, 1965], partially reduced telomere lengths during cell division lead to the ''end-replication problem'' [Shore and Bianchi, 2009]. Senescent cells show enlarged and flattened morphology and senescence-associated b-galactosidase (SA-b-gal) staining [Beausejour, 2007]. In fact, senescent cells have higher lysosomal b-gal expression, so this method can be used as a biomarker of cellular senescence [Dimri et al, 1995;Campisi and d'Adda di Fagagna, 2007].…”

Autoimmune Polyglandular Syndrome Type II After Bone Marrow Transplant: Real Transfer or Acceleration of a Programmed Disease?

“…33 This telomere-dependent pathway activating cell senescence leads to cell and tissue accumulation of autoantigens and may represent a first stimulus for autoimmune responses. 34 In addition, cell senescence may contribute to cellular mechanisms leading to impairment of donor regulatory T cells or general deficiency in hematopoietic cells (particularly lymphocytes). These phenomena might accelerate autoimmune responses and the triggering of secondary AD in the recipients (Figure 2).…”