LOCAL MITOGENIC EFFECT OF TISSUE MAST CELL SECRETION

The effect of drug-induced mast cell secretion on proliferation was studied in fibroblast-like and mesothelial-like cells in organ-cultured rat mesentery. Mast cell degranulation achieved by Compound 48/80 was followed by a marked mitogenic reaction in the surrounding tissue cells. The drug itself lacked mitogenic effect on cultured guinea-pig mesentery, the mast cells of which are unresponsive to the drug, and on a human normal fibroblast-like cell line. In contrast, histamine at about 10^?10 M, a major mast cell component, induced marked mitogenesis in guinea-pig mesentery without causing degranulation of mast cells. It is concluded that secreting rat-tissue mast cells release a mitogenic factor or factors acting locally on nearby tissue cells.     

On disturbance of homeostasis in organ-cultured tissue

Summary The intact membranous rat mesentery was cultured in Eagle's minimum essential medium containing no serum or only low concentrations of serum. The procedure is in some important respects superior to previous organ culture techniques. To estimate the extent of disturbance of homeostasis of the tissue in culture, the spontaneous mast-cell histamine release was quantitated after preculture preparation of the specimens and after different intervals in culture. Also, the proliferation of fibroblasts and mesothelial cells that predominate in the mesentery was assessed at 48 h by cytofluorometric quantitation of DNA in single-tissue cells. Spontaneous histamine release was time dependent during cultivation, amounting to ca. 50% at 48 h, and was affected by the medium used for moistening the tissue before cultivation. Culturing also brought about great spontaneous increase in the proliferation of fibroblasts and mesothelial cells, the rate being related to the concentration of serum. Addition of the mast-cell secretagogues 48/80 or polymyxin B at 1 h caused rapid release of 50 to 60% of the histamine and was followed by augmented proliferation in the serum-containing media. The spontaneous increase of cell proliferation in tissue culture may be causally related to mast-cell secretion. Further studies are needed to define factors influencing the spontaneous mast-cell secretion and the mast-cell-dependent mitogenesis in normal tissue cells Supported by grants from the Swedish Medical Research Council (Project 5942) and State Board for Animal Experiments.     

On the 48÷80-induced secretion of tissue mast cells and its mitogenic effect on nearby cells in the intact rat

Histamine release from tissue-bound mast cells and cell proliferation in the proper mesentery in the intact rat was quantitated following in intraperitoneal injection of graded doses of compound 48/80. The dose-response curves were sigmoid-like in linear-log plots. ED50 for histamine release was 0.035-0.040 and for increased cell proliferation 0.040-0.048 microgram per g BW. The proliferative response following mast-cell secretion ceased after a period of between 48-72 h, irrespective of whether a high or a low dose of 48/80 was used. Basal on the net rate of histamine synthesis (ca. 0.45 microgram/g mesentery wet weight/h) after an initial injection of 48/80, on the extent of histamine release and the proliferative response after a repeated injection of 48/80, it is concluded that there is a lag period of at least 3 days before proliferation can be re-stimulated by renewed 48/80-induced mast-cell secretion.     

Acute hyperglycaemia and mast-cell-dependent mitogenesis in rat

Hyperglycaemia is considered to be of possible aetiological significance for proliferative lesions in diabetes. We recently found that mast-cell-mediated proliferation in mesentery and skin is augmented in hyperglycaemic rats with longstanding diabetes. We now report a study to examine whether acute hyperglycaemia affects the proliferative response of fibroblasts and mesothelial cells that follows local mast-cell secretion in healthy rats. Hyperglycaemia was achieved by continuous intravenous infusion of glucose over a period of 2.5 h preceding and 9.5 h following administration of the mast-cell secretagogue compound 48/80. The 48/80 was given intraperitoneally which causes rapid mast-cell secretion and prompt subsequent mesenteric mitogenic stimulation. Hyperglycaemia thus persisted throughout the prereplicative period, during which stimulated cells are recruited into the cell cycle from a quiescent state. Because the ensuing mesenteric mitogenic response, estimated by specific DNA activity and mitosis counting, was unaffected by glucose infusion, acute hyperglycaemia itself appears to be of no aetiological significance for the accelerated mast-cell-dependent mesenteric mitogenesis in the diabetic rat.     

On the role of arachidonic acid metabolites in mast-cell mediated mitogenesis in the rat

We investigated whether the mitogenic response induced by local mast-cell secretion in the rat mesentery was affected by suppression of phospholipase A2, lipoxygenase, or cyclooxygenase in arachidonic acid metabolism. Enzyme inhibitor was given in a single intravenous dose 5 min before intraperitoneal injection of the mast-cell secretagogue 48/80. Mepacrine, a phospholipase A2 inhibitor, suppressed the generation of both leukotrienes (SRS) and prostaglandins (PG), whereas the lipoxygenase inhibitor BW 755C reduced the generation of SRS, and the cyclooxygenase inhibitor indomethacin significantly suppressed the generation of PG. None of the enzyme inhibitors affected the basal mesenteric histamine content or histamine release in the mesentery after exposure to 48/80, and none of them affected mast-cell-mediated mitogenesis in the mesentery as judged by specific DNA activity and mitosis counting. The stimulation of DNA synthesis and mitosis initiated by secreting mast cells is apparently not mediated or modulated by synthesis of leukotrienes, prostaglandins, or other known arachidonic acid metabolites.     

Mast-cell-mediated angiogenesis: a novel experimental model using the rat mesentery

The angiogenic effect of autogenous secreting mast cells (MCs) was studied using a novel experimental approach. The virtually avascular membranous rat mesentery was used as test tissue. The activation of MCs was elicited by repeated intraperitoneal injections of the MC-secretagogue compound 48/80, which per se appears inert from the proliferogenic and angiogenic point of view. Angiogenesis was quantitated histologically and expressed the number of vessels/unit length of mesentery. The smallest vessels recognized had a luminal area of approximately 7-8 microns 2 (corresponding to a circular diameter of 3.0-3.2 microns). Seven to ten days after MC-activation ended, the number of blood vessels had increased 7- to 6-fold. A retrogressive reaction occurred between days 21 and 38 after treatment, when the number of vessels had essentially normalized, as compared to vehicle-treated controls. The present study, introducing the membranous mesentery as a model for quantitative angiogenetic studies, provides evidence that MCs can induce angiogenesis, which is new. The possible therapeutic implication of this finding is noteworthy.     

Effects of degranulation of mast cells on proliferation of mesenchymal cells in the mesentery of mice

Summary A mast-cell activator, compound 48/80, causes proliferation of mesenchymal cells in the mesentery of rats. Its effect on W/W ^vmice deficient in mast cells was tested to determine whether the proliferation is mediated in the degranulation of mast cells. Incorporation of [³H]thymidine into mesenchymal cells in the mesentery of these mice with or without compound 48/80 was very small compared to their normal litter mates. However, bone marrow transplantation markedly enhanced the effect of compound 48/80, and resulted in an incorporation of [³H]thymidine almost comparable to that observed in normal mice. Our results provide evidence that mesenchymal cell proliferation is caused by a product secreted by mast cells when stimulated by compound 48/80.Supported by a Grant-in-Aid for Scientific Research, No. 366, from the Japanese Ministry of Health and WelfareThe authors are indebted to Drs. Motomu Minamiyama and Yukio Hirata for valuable advices, and to Miss Mitsuko Inoue for technical assistance     

Mast cell activation and tissue cell proliferation

Summary The effect of mast cell activation and degranulation on the proliferation in the intact mesentery was studied in Sprague-Dawley rats. Mast cell activation was achieved by a single intraperitoneal injection of Compound 48/80.The proliferation was studied using three independent methods for estimation of cell production and DNA synthesis: 1. the mitotic index, 2. the relative number of cells having a DNA content in the S and G2 regions, by Feulgen photometric measurement in individual cells, and 3. the specific DNA activity, employing a method which combines a liquid scintillation technique after an intravenous injection of ³H-thymidine and Feulgen photometric determination of the DNA content per membrane preparation.It was found that the proliferation of the normal mesenchymal cells adjacent to the activated and degranulated mast cells in the mesentery was significantly increased within 24 and 32 h, the maximum increase being more than 20-fold compared to untreated controls. The results suggest that the common type of mast cell may have a pathophysiological function related to stimulation of local cell proliferation.Supported by grants from the Swedish Medical Research Council (Project 12X-2235) and from the Medical Faculty, University of LinköpingWe thank Brita Söderlund, Margareta Odenö and Iréne Svensson for skilful technical assistance, and Erik Leander, Ph. D., for help with statistical methodsPart of this work was presented at the 7th Meeting of the European Study Group for Cell Proliferation, 5–9 May 1975, in Amsterdam, The Netherlands     

Further studies on the delayed mast-cell-mediated mitogenesis in diabetic rat

We have investigated whether the delayed augmented mast-cell-dependent mitogenesis that we recently demonstrated in the true mesentery of diabetic rats may occur also in a tissue which is essentially different both functionally and structurally. Cutaneous proliferation in insulin-deficient rats following a single intradermal injection of compound 48/80 was assessed by the specific DNA activity and mitotic index, on days 7 and 28 after giving streptozotocin. The proliferation variables, which ran parallel, indicated that mast-cell secretion was not followed by proliferation on day 7, whereas there was markedly augmented proliferation on day 28. Mitosis counting showed that cell production following mast-cell secretion was significantly increased not only in the entire cutis but also in epithelial structures (epidermis and epidermal appendages). These findings are closely similar to the delayed augmentation of mast-cell-dependent mesenteric mitogenesis in diabetic rats. It is concluded that there may be a general pattern of delay in the appearance of augmented mast-cell-mediated mitogenesis in rats with chemically induced diabetes. It is questioned whether or not this delayed mitogenesis may be connected with the postponed proliferation in a variety of tissues and organs (such as arteries, eyes, and kidneys) that occurs in experimental and clinical diabetes.     

Immunohistochemical identification of an extracellular matrix scaffold that microguides capillary sprouting in vivo.

To gain insight into how a naturally occurring scaffold composed of extracellular matrix (ECM) proteins provides directional guidance for capillary sprouting, we examined angiogenesis in whole-mount specimens of rat mesentery. Angiogenesis was studied in response to normal maturation, the injection of a mast cell degranulating substance (compound 48/80), and mild wounding. Confocal microscopy of specimens immunolabeled for elastin revealed a network of crosslinked elastic fibers with a density of 140.8 +/- 37 mm of fiber/mm(2) tissue. Fiber diameters ranged from 180 to 1400 nm, with a mean value of 710 +/- 330 nm. Capillary sprouts contained CD31- and OX-43-positive endothelial cells as well as desmin-positive pericytes. During normal maturation, leading endothelial cells and pericytes were in contact and aligned with an elastic fiber in approximately 80-90% of all sprouts. In wounding and compound 48/80-treated specimens, in which angiogenesis was markedly increased, leading endothelial cells remained in contact and aligned with elastic fibers in approximately 60-80% of all sprouts. These observations indicate that elastic fibers are used for endothelial and pericyte migration during capillary sprouting in rat mesentery. The composition of this elastic fiber matrix may provide important clues for the development of tissue-engineered scaffolds that support and directionally guide angiogenesis.     

The effect of insulin on delayed augmented mast-cell mediated mitogenesis in diabetic rats

Delayed augmented mitogenic reactivity follows mast-cell secretion in mesentery and skin in streptozotocin-diabetic rats with 4-week insulin-deficiency (Norrby 1982; Norrby et al. 1982; Norrby 1983). In such rats the basal proliferation is essentially unchanged in the mesentery and skin, whereas it is significantly increased in the small gut and significantly decreased in the kidney. On treating rats with 4-week-old diabetes with very-long-acting insulin for over 3 days (16 U/kg X 2 daily) the basal proliferation of the small gut and the kidney apparently became normal, the body weight increased, and the blood glucose concentration dropped substantially and progressively. However, insulin-treatment did not affect the mast-cell-dependent mitogenesis in the mesentery following intraperitoneal injection of the mast-cell secretagogue compound 48/80, as judged by specific DNA activity and mitosis counting. We conclude that some metabolic or cellular feature of diabetes which is not restored by 3-day insulin treatment, and not insulin deficiency itself, is the cause of the delayed increased mitogenic reactivity that follows mast-cell secretion in diabetic rat.     

Biochemical effects of 12-O-tetradecanoylphorbol-13-acetate, retinoic acid, phenobarbital, and 5-azacytidine on a normal rat liver epithelial cell line

Compound 48/80 (poly-p-methoxyphenethylmethylamine), an agent commonly used to trigger degranulation of mast cells, at concentrations of 5-20 micrograms/ml suppresses the proliferation of L1210 and Friend leukemic cells in vitro, inducing the formation of giant cells, which are polykaryons. Both the proportion of polykaryons in cultures and their size (which reflects the number of nuclei per polykaryon) increase during growth in the presence of 48/80 up to 48 hr; thereafter, the cells lose viability. A predominant number of nuclei in these polykaryons contain a 4C, or higher DNA content. The data indicate that compound 48/80 impairs the cleavage (cytokinesis) and perhaps mitotic processes. Mechanisms by which compound 48/80 induces the described effects are unknown but may be related to the polycationic nature of the polymer and its interaction with the cell membrane. Certain attributes of compound 48/80 suggest that this or similar polymers may have value as research tools for the study of regulatory mechanisms involved in cell division.     

Staining properties of duodenal mast cells in 48/80-treated rats

Summary Mast cells in the tongue, mesentery and lamina propria of the duodenal mucosa in normal and 48/80-treated rats were observed at different time intervals. The tissues were studied comparatively after staining with toluidine blue, acridine orange or alcian bluesafranin. Under the experimental conditions used, the mast cells in the tongue and mesentery showed constant positive reactions to toluidine blue and acridine orange, both of which failed to demonstrate the presence of mast cells in the lamina propria of the duodenal mucosa. The combined alcian blue-safranin stain elicited a safranin-positive reaction in the mast cells of the tongue and mesentery and an alcian blue reaction in those of the lamina propria of the duodenal mucosa. This alcianophilia of the duodenal mast cells was not affected by compound 48/80. On the other hand, the safranin stain of the tongue and mesentery mast cells was altered to alcian blue by the drug. The results are discussed in the light of recent developments in mast cell research.This work was supported by grant MA-2236 of the Medical Research Council of Canada.     

Absence of OX-43 antigen expression in invasive capillary sprouts: identification of a capillary sprout-specific endothelial phenotype

Endothelial cells exhibit a number of unique phenotypes, some of which are angiogenesis dependent. To identify a capillary sprout-specific endothelial phenotype, we labeled angiogenic rat mesentery tissue using a microvessel and capillary sprout marker (laminin), selected endothelial cell markers (CD31, tie-2, and BS-I lectin), and the OX-43 monoclonal antibody, which recognizes a 90-kDa membrane glycoprotein of unknown function. In tissues that were stimulated through wound healing and compound 48/80 application, double-immunolabeling experiments with an anti-laminin antibody revealed that the OX-43 antigen was expressed strongly in all microvessels. However, the OX-43 antigen was completely absent from a large percentage (>85%) of the capillary sprouts that were invading the avascular tissue space. In contrast, sprouts that were introverting back into the previously vascularized tissue retained high levels of OX-43 antigen expression. Double-labeling experiments with endothelial markers indicated that the OX-43 antigen was expressed by microvessel endothelium but was absent from virtually all invasive capillary sprout endothelial cells. We conclude that the absence of OX-43 antigen expression marks a novel, capillary sprout-specific, endothelial cell phenotype. Endothelial cells of this phenotype are particularly abundant in capillary sprouts that invade avascular tissue during angiogenesis.     

Growth factor stimulated cell proliferation is accompanied by an elevated labile intracellular pool of zinc in 3T3 cells

Growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and insulin-like growth factor-I (IGF-I) are required for quiescent 3T3 cells to proliferate, but zinc deprivation impairs IGF-I-induced DNA synthesis. We recently showed that labile intracellular pool of zinc is involved in cell proliferation. Our objective was to determine whether the labile intracellular pool of zinc plays a role in growth factor (PDGF, EGF, and IGF-I)-stimulated proliferation of 3T3 cells. Quiescent 3T3 cells were cultured in DMEM with or without growth factors. Labile intracellular pool of zinc, DNA synthesis, and cell proliferation were assessed using fluorescence microscopy, 3H-thymidine incorporation, and total cell number counts, respectively. After 24 h, growth factors stimulated DNA synthesis (24%) but not cell proliferation. After 48 h, growth factors stimulated both DNA synthesis (37%) and cell proliferation (89%). In response to growth factor stimulation, the labile intracellular pool of zinc was also elevated after 24 or 48 h of treatment. In summary, growth factor (PDGF, EGF, and IGF-I)-stimulated increase in DNA synthesis and cell proliferation were accompanied by an elevated labile intracellular pool of zinc in 3T3 cells. Since elevation of the labile intracellular pool of zinc occurred along with increased DNA synthesis, but cell proliferation remained unchanged, the elevation of the labile intracellular pool of zinc likely occurred during the S phase to provide the zinc needed to support DNA synthesis and ultimately cell proliferation.     

Accelerated wound repair, cell proliferation, and collagen accumulation are produced by a cartilage-derived growth factor

Cartilage-derived growth factor (CDGF), a cationic polypeptide of approximately 18,000 mol wt, was prepared from bovine articular cartilage; other sources were bovine and human scapular and costal cartilage. Previous studies have shown that CDGF stimulates the proliferation of cultured mouse fibroblasts as well as chondrocytes and endothelial cells from various sources. In this study, CDGF was shown to stimulate dose-dependently the accumulation of DNA and collagen by rat embryo fibroblasts and a population of fibroblasts derived from granulation tissue. CDGF also stimulated the proliferation of cultured bovine capillary endothelial cells dose-dependently. To evaluate the effects of CDGF in vivo, we implanted polyvinyl alcohol sponges subcutaneously in rats. 6 d postimplantation, sponges were injected with 300 micrograms of partially purified CDGF, a dose which takes into account the cell numbers in the sponges as compared with cell cultures. CDGF rapidly disappeared from the sponges and only approximately 10% of the initial dose was present at 4 h. Despite its transient presence, CDGF caused a relative increase in sponge DNA content of 2.6-fold at 48 h and 2.4-fold at 72 h. We repeated the sponge experiment by using 500-ng injections of CDGF purified to near homogeneity by heparin-Sepharose chromatography. Purified CDGF caused significant increases in sponge collagen, protein, and DNA content at 48 and 72 h after a single injection. The effects of CDGF were abolished by heat and unaffected by reduction of disulfide linkages. Morphologically, CDGF did not evoke an inflammatory response, and its effect on proliferating endothelial cells and fibroblasts was, therefore, probably direct. However, increases in DNA content of sponges could not be fully accounted for by increased DNA synthesis, which suggests that recruitment may be an important component of the in vivo response. Taken together, the effects of CDGF on cultured cells and granulation tissue suggest that the sustained presence of CDGF in vivo may greatly enhance its effects upon wound repair.     

Cellular and extracellular changes following mast-cell secretion in avascular rat mesentery

Summary Mast cell (MC) secretion induces local cell proliferation lasting 48–72 h in fibroblasts and mesothelial cells in the almost avascular true mesentery of the rat. We studied this membranous tissue by transmission electron microscopy with regard to cellular and extracellular features occurring during the first 72 h following MC secretion.After MC secretion elicited by compound 48/80, apparently all individual tissuebound cells (i.e. fibroblasts, mesothelial cells, and macrophages) show signs of accelerated metabolic activity. In fibroblasts, conspicuous increases in the volume of Golgi apparatus and rough endoplasmic reticulum and in the amount of plasmalemmal indentations suggest an increased production and secretion of the extracellular matrix. Released MC granules lying close to projections of nearby phagocytosing cells cause areas free from electrondense material in the extracellular matrix. MC secretion therefore appears to produce a remodelling of extracellular matrix. Most of the activities initiated by MC secretion start to subside within (48-)72 h.The findings indicate a close functional relationship between the tissue MC and all its neighbouring cells and the surrounding extracellular matrix. The striking chain of events that it induces emphasizes strongly that the secreting MC plays a prominent although as yet in many respects enigmatic role in normal tissue.Key to Abbreviations CM cytoplasmic matrix - GA Golgi apparatus - MC mast cell - PL primary lysosome - RER rough endoplasmic reticulum - TEM transmission electron microscopy Supported by grants from the Swedish Medical Research Council, Project 5942     

Isolation of an autocrine growth factor from hepatoma HTC-SR cells

A growth factor has been isolated from HTC-SR rat hepatoma tissue culture cells which specifically stimulates DNA synthesis and cell proliferation of the HTC cells that produce it. The factor can be isolated from HTC cell conditioned medium or from an HTC cell extract. This autocrine factor has been purified 640-fold from a postmicrosomal supernatant by successive steps, involving ethanol precipitation, heating at 80 degrees C for 10 min, chromatography on a DEAE Bio-Gel A column, and chromatography on a heparin-sepharose affinity column. The major peak of activity eluted from the heparin column migrates as a single band on SDS-PAGE with an apparent Mr of 60,000. The factor is resistant to acid, heat, and neuraminidase but sensitive to trypsin, papain, and protease. The autocrine nature of the factor is indicated by the finding that several other types of cells do not respond with increased DNA synthesis. Mouse L-cells, BHK cells, Novikoff hepatoma cells, hepatocytes in primary culture, and an epithelial-like rat liver-derived cell line (Clone 9) were tested, and none of the cells could be stimulated. Small amounts of the factor could be extracted from the Clone 9 cells, however. This material had the same physical and purification properties as the factor extracted from HTC cells, but it did not stimulate DNA synthesis in Clone 9 cells, only in HTC cells. Addition of the factor resulted in an almost immediate stimulation of DNA synthesis in a proliferating HTC cell population. When the factor was added together with [3H]thymidine for 2 h, a significant stimulation of DNA synthesis was observed, provided the addition was made between 18 and 48 h after the cells had been plated. Autoradiographic studies indicated that the factor both accelerates DNA synthesis in cells already making DNA and increases the number of cells entering the S period. The stimulation of DNA synthesis was completely inhibited by 10 mM hydroxyurea, whether the factor was present for 2, 24, or 48 h in the culture. A significant increase in cell number due to addition of the factor was also observed. This accelerated proliferation was detectable only after the cells had been in culture for at least 48 h with the factor present.     

Different proliferative responsiveness of fibroblasts and mesothelial cells in the rat mesentery following administration of compound 48/80 at various hours of the day.

The proliferative responsiveness of fibrolasts and mesothelial cells in the mesenterial membrane of normal rats was studied quantitatively after a single i.p. injection of the mast-cell activating and histamine-releasing drug Compound 48/80. To make some allowance for a possible chronobiologic effect of the circadian type on the induced proliferation, the drug was given at 1 a.m., 9 a.m., or 5 p.m., and the animals were examined 16, 24, and 32 h later. The proliferation was estimated by cytophotometric Feulgen DNA measurements in individual fibroblast and mesothelial cell nuclei, and by mitotic frequency counting. The main result was that a larger fraction of fibroblasts than of mesothelial cells was stimulated to proliferation, regardless of the hour of treatment with Compound 48/80. It was further demonstrated that in control animals the fraction of cells of either fibroblastic or mesothelial type present in the S cum G2 cell-cycle phases varied markedly at different hours of the day. Quantitative differences appeared in the induced proliferation with regard to the hour of treatment. The most vigorous proliferative response appeared after administration of the drug at 9 a.m. The fraction of cells in the S cum G2 cell-cycle phases was then increased at 16 h and the fraction of dividing cells at 24 h after treatment, illustrating the promptness of the induced proliferative reaction.     

Postmitotic neurons develop a p21‐dependent senescence‐like phenotype driven by a DNA damage response

In senescent cells, a DNA damage response drives not only irreversible loss of replicative capacity but also production and secretion of reactive oxygen species (ROS) and bioactive peptides including pro‐inflammatory cytokines. This makes senescent cells a potential cause of tissue functional decline in aging. To our knowledge, we show here for the first time evidence suggesting that DNA damage induces a senescence‐like state in mature postmitotic neurons in vivo. About 40–80% of Purkinje neurons and 20–40% of cortical, hippocampal and peripheral neurons in the myenteric plexus from old C57Bl/6 mice showed severe DNA damage, activated p38MAPkinase, high ROS production and oxidative damage, interleukin IL‐6 production, heterochromatinization and senescence‐associated β‐galactosidase activity. Frequencies of these senescence‐like neurons increased with age. Short‐term caloric restriction tended to decrease frequencies of positive cells. The phenotype was aggravated in brains of late‐generation TERC?/? mice with dysfunctional telomeres. It was fully rescued by loss of p21(CDKN1A) function in late‐generation TERC?/?CDKN1A?/? mice, indicating p21 as the necessary signal transducer between DNA damage response and senescence‐like phenotype in neurons, as in senescing fibroblasts and other proliferation‐competent cells. We conclude that a senescence‐like phenotype is possibly not restricted to proliferation‐competent cells. Rather, dysfunctional telomeres and/or accumulated DNA damage can induce a DNA damage response leading to a phenotype in postmitotic neurons that resembles cell senescence in multiple features. Senescence‐like neurons might be a source of oxidative and inflammatory stress and a contributor to brain aging.