Cell cycle of globose basal cells in rat olfactory epithelium
TL;DR: It is reported here that the globose basal cells in olfactory epithelium of rats, as in mice, are the predominant type of proliferating cell, and account for 97.6% of the actively dividing cells in the basal compartment of the normal epithelia.
Abstract: The olfactory epithelium of adult mammals has the unique property of generating olfactory sensory neurons throughout life. Cells of the basal compartment, which include horizontal and globose basal cells, are responsible for the ongoing process of neurogenesis in this system. We report here that the globose basal cells in olfactory epithelium of rats, as in mice, are the predominant type of proliferating cell, and account for 97.6% of the actively dividing cells in the basal compartment of the normal epithelium. Globose basal cells have not been fully characterized in terms of their proliferative properties, and the dynamic aspects of neurogenesis are not well understood. As a consequence, it is uncertain whether cell kinetic properties are under any regulation that could affect the rate of neurogenesis. To address this gap in our knowledge, we have determined the duration of both the synthesis phase (S-phase) and the full cell cycle of globose basal cells in adult rats. The duration of the S-phase was found to be 9 hr in experiments utilizing sequential injections of either IdU followed by BrdU or 3H-thy followed by BrdU. The duration of the cell cycle was determined by varying the time interval between the injections of 3H-thy and BrdU and tracking the set of cells that exit S shortly after the first injection. With this paradigm, the interval required for these cells to traverse G2, M, G1, and a second S-phase, is equivalent to the duration of one mitotic cycle and equals 17 hr. These observations serve as the foundation to assess whether the cell cycle duration is subject to regulation in response to experimental injury, and whether such regulation is partly responsible for changes in the rate of neurogenesis in such settings.
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TL;DR: Cell renewal in the epithelium is directed to replace neurons when they die in normal animals and does so at an accelerated pace after damage to the olfactory nerve, and multiple growth factors are likely to be central in regulating choice points in epitheliopoiesis.
Abstract: The peripheral olfactory system is able to recover after injury, i.e., the olfactory epithelium reconstitutes, the olfactory nerve regenerates, and the olfactory bulb is reinnervated, with a facility that is unique within the mammalian nervous system. Cell renewal in the epithelium is directed to replace neurons when they die in normal animals and does so at an accelerated pace after damage to the olfactory nerve. Neurogenesis persists because neuron-competent progenitor cells, including transit amplifying and immediate neuronal precursors, are maintained within the population of globose basal cells. Notwithstanding events in the neuron-depleted epithelium, the death of both non-neuronal cells and neurons directs multipotent globose basal cell progenitors, to give rise individually to sustentacular cells and horizontal basal cells as well as neurons. Multiple growth factors, including TGF-α, FGF2, BMPs, and TGF-βs, are likely to be central in regulating choice points in epitheliopoiesis. Reinnervation of the bulb is rapid and robust. When the nerve is left undisturbed, i.e., by lesioning the epithelium directly, the projection of the reconstituted epithelium onto the bulb is restored to near-normal with respect to rhinotopy and in the targeting of odorant receptor-defined neuronal classes to small clusters of glomeruli in the bulb. However, at its ultimate level, i.e., the convergence of axons expressing the same odorant receptor onto one or a few glomeruli, specificity is not restored unless a substantial number of fibers of the same type are spared. Rather, odorant receptor-defined subclasses of neurons innervate an excessive number of glomeruli in the rough vicinity of their original glomerular targets. Anat Rec (New Anat) 269:33–49, 2002. © 2002 Wiley-Liss, Inc.
468 citations
Cites background from "Cell cycle of globose basal cells i..."
...GBCs exhibit a high proliferative rate, such that the vast majority of cells labeled by the incorporation of thymidine analogues in the normal adult epithelium are GBCs (Schwartz Levey et al., 1991; Huard and Schwob, 1995)....
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TL;DR: It is suggested that granule cell death stimulates the proliferation of precursor cells, many of which survive and differentiate into mature granule neurons.
424 citations
TL;DR: A brief overview of comparative nasal structure, function and toxicologic pathology of the mammalian nasal epithelium is provided and a brief discussion on how data from animal toxicology studies have been used to estimate the risk of inhaled chemicals to human health is discussed.
Abstract: The nose is a very complex organ with multiple functions that include not only olfaction, but also the conditioning (e.g., humidifying, warming, and filtering) of inhaled air. The nose is also a "scrubbing tower" that removes inhaled chemicals that may be harmful to the more sensitive tissues in the lower tracheobronchial airways and pulmonary parenchyma. Because the nasal airway may also be a prime target for many inhaled toxicants, it is important to understand the comparative aspects of nasal structure and function among laboratory animals commonly used in inhalation toxicology studies, and how nasal tissues and cells in these mammalian species may respond to inhaled toxicants. The surface epithelium lining the nasal passages is often the first tissue in the nose to be directly injured by inhaled toxicants. Five morphologically and functionally distinct epithelia line the mammalian nasal passages--olfactory, respiratory, squamous, transitional, and lymphoepithelial--and each nasal epithelium may be injured by an inhaled toxicant. Toxicant-induced epithelial lesions in the nasal passages of laboratory animals (and humans) are often site-specific and dependent on the intranasal regional dose of the inhaled chemical and the sensitivity of the nasal epithelial tissue to the specific chemical. In this brief review, we present examples of nonneoplastic epithelial lesions (e.g., cell death, hyperplasia, metaplasia) caused by single or repeated exposure to various inhaled chemical toxicants. In addition, we provide examples of how nasal maps may be used to record the character, magnitude and distribution of toxicant-induced epithelial injury in the nasal airways of laboratory animals. Intranasal mapping of nasal histopathology (or molecular and biochemical alterations to the nasal mucosa) may be used along with innovative dosimetric models to determine dose/response relationships and to understand if site-specific lesions are driven primarily by airflow, by tissue sensitivity, or by another mechanism of toxicity. The present review provides a brief overview of comparative nasal structure, function and toxicologic pathology of the mammalian nasal epithelium and a brief discussion on how data from animal toxicology studies have been used to estimate the risk of inhaled chemicals to human health.
404 citations
Cites background from "Cell cycle of globose basal cells i..."
...The constant turnover of OSNs is due to the capacity of progenitor cells in the basal cell layer of the OE to proliferate and differentiate into mature OSNs (Mackay-Sim and Kittel, 1991; Huard and Schwob, 1995; Schwob et al., 1995; Huard et al., 1998; Jang et al., 2003; Schwob, 2005)....
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TL;DR: IGF-I functions as a putative regenerative agent in the adult CNS and is found to increase progenitor cell proliferation and new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus.
Abstract: Apart from regulating somatic growth and metabolic processes, accumulating evidence suggests that the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis is involved in the regulation of brain growth, development, and myelination. In addition, both GH and IGF-I affect cognition and biochemistry in the adult brain. Some of the effects of GH are attributable to circulating IGF-I, while others may be due to IGF-I produced locally within the brain. Some of the shared effects in common to GH and IGF-I may also be explained by cross-talk between the GH and IGF-I transduction pathways, as indicated by recent data from other cell systems. Otherwise, it also seems that GH may act directly without involving IGF-I (either circulating or locally). Plasticity in the central nervous system (CNS) may be viewed as changes in the functional interplay between the major cell types, neurons, astrocytes, and oligodendrocytes. GH and IGF-I affect all three of these cell types in several ways. Apart from the neuroprotective effects of GH and IGF-I posited in different experimental models of CNS injury, IGF-I has been found to increase progenitor cell proliferation and new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. It appears that the MAPK signaling pathway is required for IGF-I-stimulated proliferation in vitro, whereas the PI3K/Akt or MAPK/Erk signaling pathway appears to mediate antiapoptotic effects. The increase of IGF-I on endothelial cell phenotype may explain the increase in cerebral arteriole density observed after GH treatment. The functional role of GH and IGF-I in the adult brain will be reviewed with reference to neurotransmitters, glucose metabolism, cerebral blood flow, gap junctional communication, dendritic arborization, exercise, enriched environment, depression, learning, memory, and aging. Briefly, these findings suggest that IGF-I functions as a putative regenerative agent in the adult CNS. Hitherto less studied regarding in these aspects, GH may have similar effects, especially as it is the main regulator of IGF-I in vivo. Some of the positive cognitive features of GH treatment are likely attributable to the mechanisms reviewed here.
353 citations
TL;DR: It is concluded that the balance between multipotency and selective neuropotency, which is characteristic of globose basal cells in the normal olfactory epithelium, is determined by which cell types have been depleted and need to be replenished rapidly.
Abstract: We have infused replication-incompetent retroviral vectors into the nasal cavity of adult rats 1 day after exposure to the olfactotoxic gas methyl bromide (MeBr) to assess the lineage relationships of cells in the regenerating olfactory epithelium. The vast majority of the retrovirus-labeled clones fall into three broad categories: clones that invariably contain globose basal cells (GBCs) and/or neurons, clones that always include cells in the ducts of Bowman's glands, and clones that are composed of sustentacular cells only. Many of the GBC-related clones contain sustentacular cells and horizontal basal cells as well. Most of the duct-related clones contain gland cells, and some also include sustentacular cells. Thus, the destruction of both neurons and non-neuronal cells that is caused by MeBr activates two distinct types of multipotent cells. The multipotent progenitor that gives rise to neurons and non-neuronal cells is a basal cell, whereas the progenitor that gives rise to duct, gland, and sustentacular cells resides within the ducts, based on the pattern of sparing after lesion and the analysis of early regeneration by using cell type-specific markers. We conclude that the balance between multipotency and selective neuropotency, which is characteristic of globose basal cells in the normal olfactory epithelium, is determined by which cell types have been depleted and need to be replenished rapidly.
296 citations
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TL;DR: The morphological stages of maturation and ageing of this exceptional neuron have been described both at light and electron microscopical levels and the neural elements have been classified as: basal cells proper, globose basal cells, and neurons.
Abstract: The neurogenetic process leading to the formation of primary sensory neurons persists into adult life in the olfactory epithelium of mammals. The morphological stages of maturation and ageing of this exceptional neuron have been described both at light and electron microscopical levels. For descriptive purposes the neural elements have been classified as: (1) basal cells proper, (2) globose basal cells, and (3) neurons. Intermediate stages, however, have been identified. Autoradiographic observations complement the morphological studies and provide a time sequence of the morphological stages leading to the mature neurons. A typical columnar arrangement of the sensory neurons has been described. Furthermore, active and quiescent zones have been recognized in the neuroepithelium. In the active zones the neurogenetic process is vigorous, and the zones are characterized by the presence of immature elements. However, in the quiescent zones there exists a population of mature elements while immature neurons are sparse.
964 citations
TL;DR: The retrograde degeneration affecting olfactory sensory neurons of rats after severance of their axons is described and the reconstitution of new neurons originating from stem cells located at the base of the Olfactory neuroepithelium is illustrated.
Abstract: This report describes the retrograde degeneration affecting olfactory sensory neurons of rats after severance of their axons and illustrates the reconstitution of new neurons originating from stem cells located at the base of the olfactory neuroepithelium. Degeneration of the mature, axotomized neurons, signalled by an increased electron density of their cytoplasmic matrix and by the appearance of lipofuscin-like granules, can be detected in the neuroepithelium as early as 24 h after surgery and becomes conspicuous between the second and the third day. Degenerating neurons can be observed in decreasing number up to the tenth post-operative day. They are removed by macrophages which invade the epithelium. The reconstitution of new neurons begins to occur after eight days, when the stem cells undergo vigorous mitotic activity and differentiate into neurons. The morphology of the reconstituted neurons has been described in detail at different stages of their maturation. After 30 days, the olfactory epithelium appears similar to controls. On the basis of both morphological (in rats) and autoradiographic ( in mice) observations, the basal cells have been recognized as stem cells of the olfactory neurons.
525 citations
TL;DR: Development of a culture system for mammalian olfactory epithelium has permitted the process of neurogenesis to be examined in vitro, and data are presented which suggest that the precursor follows a simple lineage program, dividing to give rise to two N-CAM+ daughter neurons.
386 citations
TL;DR: The data suggest, at least in young rats, that horizontal basal cells are not precursors of olfactory neurons, that there is a lineage path from globose cells to mature neurons, and that sustentacular cells may arise from a separate lineage.
330 citations
TL;DR: It is concluded that life-span is significantly shorter for olfactory neurons born in the targetless epithelium and that ofactory neurons are trophically dependent on the presence of the bulb for their prolonged survival.
Abstract: In most neural systems, developing neurons are trophically dependent on contact with their synaptic target for their survival and for some features of their differentiation. However, in the olfactory system, it is unclear whether or not the survival and differentiation of olfactory sensory neurons depend on contact with the olfactory bulb (normally the sole synaptic target for these neurons). In order to address this issue, we examined neuronal life-span and differentiation in adult rats subjected to unilateral olfactory bulb ablation at least 1 month prior to use. Life-span of a newly generated cohort of olfactory neurons was determined by labeling them at their “birth” via the incorporation of 3H-thymidine. In the absence of the bulb, neurons are continually produced at a twofold greater rate. However, the epithelium on the ablated side is thinner, indicating that average neuronal life-span must be reduced in the targetless epithelium. Indeed, nearly 90% of the labeled neurons disappear from the bulbectomized side between 5 d and 2 weeks of neuronal age. Moreover, on electron microscopic examination, olfactory axons are degenerating in large numbers on the ablated side. Since labeled neurons migrate apically through the width of the epithelium during this same period, it appears that most, if not all, neurons on the ablated side have a life-span on the order of 2 weeks or less. In contrast, there is a more moderate degree of neuronal loss on the unoperated side of the same animals during the first 2 weeks after tracer injection, and that occurs while the neurons are concentrated in the deeper half of the epithelium, suggesting that there is a preexisting population of neurons in the control epithelium that does not die during this period. Likewise, degenerating axons are much less frequent on the unoperated side. We conclude that life-span is significantly shorter for olfactory neurons born in the targetless epithelium and that olfactory neurons are trophically dependent on the presence of the bulb for their prolonged survival. Neuronal differentiation in the absence of the bulb was assessed according to ultrastructural criteria and the pattern of protein expression using antisera to the growth associated protein GAP-43 and the olfactory marker protein. By both measures, most neurons in the epithelium on the bulbectomized side, but not all, are immature.(ABSTRACT TRUNCATED AT 400 WORDS)
299 citations