Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cells

Abstract

Hematopoietic cells are often exposed to transient hypoxia and reoxygenation as they develop and migrate. Given that bone marrow (BM) failure occurred in patients with Fanconi anemia (FA), we reason that hypoxia-then-reoxygenation represents a physiologically relevant stress for FA hematopoietic progenitor/stem cells. Here we show that expansion of Fancc-/- BM cells enriched for progenitor and stem cells was significantly decreased after 2 continuous cycles of hyperoxic-hypoxic-hyperoxic treatments compared with wild-type (WT) BM cells. This inhibition was attributable to a marked decrease of lineage-depleted (Lin-) ScaI- c-kit+ cells and more primitive Lin- ScaI+ c-kit+ cells in Fancc-/- BM cells following reoxygenation. Evaluation of the cell-cycle profile of long-term BM culture (LTBMC) revealed that a vast majority (70.6%) of reoxygenated Fancc-/- LTBMC cells was residing in the G0 and G1 phases compared with 55.8% in WT LTBMC cells. Fancc-/- LTBMC cells stained intensely for SA-beta-galactosidase activity, a biomarker for senescence; this was associated with increased expression of senescence-associated proteins p53 and p21(WAF1/CIP1). Taken together, these results suggest that reoxygenation induces premature senescence in Fancc-/- BM hematopoietic cells by signaling through p53, up-regulating p21, and causing senescent cell-cycle arrest. Thus, reoxygenation-induced premature senescence may be a novel mechanism underlying hematopoietic cell depletion and BM failure in FA.

Cytokinesis failure occurs in Fanconi anemia pathway–deficient murine and human bone marrow hematopoietic cells

“…Depletion of bone marrow cells, leading to bone marrow failure, is partly attributed to senescence and/or apoptosis of the HSCs (2,3). Senescence has been observed in bone marrow HSCs from FA mice after exposure to repetitive hyperoxiahypoxia treatments (4). The origin of apoptosis remains unclear and may have diverse underlying causes.…”

Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence

“…It has been suggested that HSC senescence plays an important role in the pathophysiology of hematologic diseases, such as aplastic anemia and MDS (Maciejewski and Risitano, 2003;Zhang et al, 2005a;Zhang et al, 2005b). To determine whether HSC senescence is a defining feature of TNF␣-mediated hematopoietic suppression, we examined two established senescence markers: senescence-associated ␤-galactosidase (SA-␤-gal) (Dimri et al, 1995) and senescenceassociated heterochromatin foci (Narita et al, 2003).…”

Effect of CPAP on Oxidative Stress and Circulating Progenitor Cell Levels in Sleep Patients With Apnea-Hypopnea Syndrome

“…Hypoxia/re-oxygenation induces damage and apoptosis in human cells, 20 and continuous cycles of hypoxia/re-oxygenation can increase the production of oxidants. 18 We found that markers of protection against oxidation correlated positively with the levels of CD45Ϫ, CD34ϩ, KDRϩ, and CD133ϩ cells, whereas the levels of superoxide anion correlated negatively. After one month of CPAP treatment, oxidative stress variables decreased and CD45Ϫ, CD34ϩ, KDRϩ, and CD133ϩ cell levels increased.…”

“…Sleep apneahypopnea syndrome is characterized by long-term sleep deprivation, which increases reactive oxygen species generation, inhibits antioxidant defense systems, and inactivates mitochondrial enzymes, thereby promoting oxidative stress. 18 In our subjects, CPAP reduced cellular oxidative stress variables and increased intracellular glutathione and mitochondrial membrane potential, which are markers of protection against oxidative stress. These results confirm that normalizing hypoxia with CPAP reduces oxidative stress.…”