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PubMed1991

Dendritic morphology and development in the ferret lateral superior olivary nucleus.

The dendritic morphology of cells in the lateral superior olivary nucleus was studied with the Golgi method in adult and postnatal ferrets. The lateral superior olivary nucleus in the adult ferret is a convoluted structure with an M-shape in frontal sections. The major cell type appears to have disk-shaped dendritic trees. Most dendritic trees appear to be approximately orthogonal to the curved medial-lateral axis of the nucleus. Depending on their position in the limb and on the plane of section with respect to the dendritic tree, the disk-shaped cells are either bipolar or radiate in orientation. One subclass of disk-shaped cells has secondary dendritic branches that end as tufts of tendril-like processes. In a second subclass of cells, the dendrites exhibit several orders of dichotomous branching and lack obvious tufts of terminal processes. Marginal cells are observed at the border of the nucleus and have dendrites restricted to the margins of the cell plate. The bipolar orientation of disk-shaped cells orthogonal to the axis of the limbs is already apparent by the time of birth. Transient spines and other appendages are abundant on somata and dendrites during the first postnatal week. By the end of the first postnatal month only distal appendages are found. Tufts of fine tendril-like processes appear at the ends of dendrites between postnatal days 28 and 56.

Animals↗

PubMed1992

Effects of sex and androgen treatment on dendritic dimensions of neurons in the sexually dimorphic preoptic/anterior hypothalamic area of male and female ferrets.

A sexually dimorphic group of cells at the dorsal border of the preoptic/anterior hypothalamic area (POA/AH) of ferrets has been previously identified in Nissl-stained tissue. In this study, Golgi-stained tissue was examined in order 1) to determine whether sex differences exist in dendritic dimensions of neurons from this region, and 2) to assess the effects of adult androgen treatment on dendritic morphology in ferrets of both sexes. Brains from adult ferrets given daily injections of testosterone propionate (5 mg/kg body weight) or oil vehicle for 5 weeks after gonadectomy were impregnated by Golgi-Cox procedures. After sectioning at 120 microns, 78 multipolar neurons were selected from the sexually dimorphic POA/AH of 12 ferrets and reconstructed in three dimensions with the aid of a computer-assisted neuron tracing system. Large sex differences were observed in somal area and most aspects of dendritic morphology, including total length, number of branches, and total dendritic surface area. Androgen also appeared to accentuate dendritic arborization in both sexes, but this effect was weaker than the sex effect, more apparent in males than females, and restricted to fewer variables. The most statistically significant effects of adult androgen treatment in males were found for total dendritic surface area and percentage of fourth order dendrites, and in females, average dendritic thickness. These data show that strong sex differences exist in dendritic structure of neurons in the POA/AH, and suggest that alterations in levels of gonadal steroids in adulthood may promote synaptic remodeling in a region of the brain involved in the control of sexually dimorphic behaviors.

Animals↗

PubMed1995

Analysis of dendritic spines in rat CA1 pyramidal cells intracellularly filled with a fluorescent dye.

The dendritic branching pattern and the distribution of dendritic spines were studied in hippocampal neurones with an improved technique. In slices taken from adult Wistar rats, CA1 pyramidal cells were filled with Lucifer yellow and examined under a laser-scanning confocal microscope. The basal dendrites were found evenly distributed inside a regular cupola-shaped volume. Their total length was about 4,500 microns. The branches divided between one and three times, with the initial segments comprising less than 2%, and the long terminal segments (mean length, 119 microns) including more than 80% of the total length of the basal dendrites. The apical dendritic branches emerged obliquely from the main shaft, ran for a distance of 50 to 250 microns, and made up a total length of about 5,100 microns in stratum radiatum and between 1,100 and 3,200 microns in stratum lacunosum-moleculare. The mean total length of the dendritic tree was 11,900 microns. All values were corrected for shrinkage. Shrinkage was measured in three dimensions and was 20.2% in the horizontal (x/y) plane and 40.9% in the vertical (z) plane. Both the basal and the apical dendritic branches were covered by regularly spaced spines. When corrected for dehydration-induced shrinkage and for hidden spines, the density was 1.80 and 2.00 spines/microns dendritic length for the basal and apical dendritic branches, respectively. Apart from the initial parts of the branches, which had few or no spines, the spines were remarkably evenly spaced. In particular, the distance between spine heads was significantly different from a random distribution, suggesting a regulatory process for the spacing of spines.

Animals↗

PubMed1989

Human tonsillar dendritic cell-induced T cell responses: analysis of molecular mechanisms using monoclonal antibodies.

Dendritic cells, isolated from human tonsillar tissue, were found to be potent stimulators of the sodium periodate T cell oxidative mitogenesis reaction. Monoclonal antibodies against CD2, CD4, CD11a, CD18, LFA-3, ICAM-1, class I and class II major histocompatibility complex (MHC) inhibited T cell proliferation in this response, whereas antibodies against CD8, CD11b, CD11c and CD16 had no effect. Further, antibodies against CD2, CD11a, CD18, LFA-3 and ICAM-1 inhibited the early dendritic cell-T cell clustering event which occurs in this cell interaction. In contrast, antibodies against CD4, class I and class II MHC did not inhibit clustering. Studies examining the expression of the respective molecules upon isolated dendritic cells and T cells suggest that anti-LFA-3 and anti-class II MHC antibodies inhibit at the level of the dendritic cell, whereas anti-CD2 and anti-CD4 antibodies inhibit at the level of the T cell. However, antibodies against CD11a, CD18, ICAM-1 and class I MHC may inhibit at either or both cell levels. These findings have enabled us to propose a molecular mechanism for dendritic cell-T cell interaction in oxidative mitogenesis. Dendritic cell-T cell clustering is mediated by bidirectional binding of LFA-1 (CD11a and CD18) and ICAM-1 (involving both molecules on both cell types) and unidirectional binding of CD2 and LFA-3 (involving T cell CD2 and dendritic cell LFA-3). This initial event permits a second interaction of dendritic cell and T cell molecules, involving T cell CD4, class I MHC (possibly at both cellular levels) and dendritic cell class II MHC, which deliver the signal for proliferation.

Antibodies, Monoclonal↗

PubMed1992

Processing and presentation of intact hen egg-white lysozyme by dendritic cells.

Dendritic cells in lymphoid tissues are of key importance as highly specialized antigen-presenting cells for the induction of T lymphocyte responses. Conflicting results have been published regarding antigen processing of intact proteins by dendritic cells. We now report that highly purified dendritic cells isolated from H-2k mouse spleens very efficiently generated immunogenic fragments of intact hen egg-white lysozyme (HEL) protein to present to an I-Ak-restricted T hybridoma cell line, specific for HEL peptide 46-61. Dendritic cells required 100 times less HEL protein than lipopolysaccharide-induced B cell blasts for effective presentation. Uptake of 125I-labeled HEL protein by dendritic cells and inhibition of presentation of HEL protein by chloroquine treatment was observed. This indicates an endocytotic process and the involvement of acidified compartments. Since the supernatant of dendritic cells, that were incubated with intact HEL protein, contained immunogenic fragments, further evidence for processing of HEL protein by dendritic cells was obtained. When HEL protein was covalently coupled to beads, dendritic cells were not able to ingest these beads, but could still process HEL protein for presentation. This suggests cell surface processing of HEL protein, although internalization of HEL protein released from the beads cannot be excluded. Taken together, these data show that H-2k dendritic cells are capable of processing and presenting intact HEL protein.

Animals↗

PubMed1995

Dendritic cells in Leishmania major-immune mice harbor persistent parasites and mediate an antigen-specific T cell immune response.

Upon infection with Leishmania major, a cause of human cutaneous leishmaniasis, mice of resistant strains are able to control the infection, with lesions resolving spontaneously. A long-lasting cell-mediated immunity protects them from reinfection. Nevertheless, small numbers of viable parasites persist in the lymph nodes of these mice. We have recently documented that, in addition to macrophages, epidermal Langerhans cells can ingest L. major. Furthermore, Langerhans cells have the unique ability to transport viable parasites from the infected skin to the draining lymph node for presentation to antigen-specific T cells and initiation of the cellular immune response. During migration, Langerhans cells develop into dendritic cells. In the present study, we analyzed whether dendritic cells support the persistence of parasites in immune hosts. Immunohistological studies and assays in vitro showed that in the lymph nodes of mice that have recovered from infection with L. major, both macrophages and dendritic cells harbor viable parasites. However, only dendritic cells were able to induce a vigorous T-cell immune response to L. major in vitro in the absence of exogenous antigen. Tracking experiments conducted in vivo suggested that the infected dendritic cells in the lymph nodes are derived from Langerhans cells that have emigrated from the skin. The data demonstrate that L. major-infected dendritic cells and macrophages in lymph nodes of immune animals represent long-term host cells, but only dendritic cells have the ability to present endogenous parasite antigen to T cells. Long-term infected dendritic cells may thus allow the sustained stimulation of a population of parasite-specific T cells, protecting the mice from reinfection. Our results favor the hypothesis that the persistence of antigen supports the maintenance of T cell memory and that dendritic cells are critically involved in this process.

Animals↗

PubMed2003

Statistical morphological analysis of hippocampal principal neurons indicates cell-specific repulsion of dendrites from their own cell.

Traditionally, the sources of guidance cues for dendritic outgrowth are mainly associated with external bodies (A) rather than with the same neuron from which dendrites originate (B). To quantify the relationship between factors A and B as determinants of the adult dendritic shape, the morphology of 83 intracellularly characterized, stained, completely reconstructed, and digitized principal neurons of the rat hippocampus was statistically analyzed using Bayesian optimization. It was found that the dominant directional preference (tropism) manifested in dendritic turns is to grow away from the soma rather than toward the incoming fibers or in any other fixed direction; therefore, B is predominant. Results are robust and consistent for all examined morphological classes (dentate gyrus granule cells, basal and apical trees of CA3 and CA1 pyramidal cells). In addition, computer remodeling of neurons based on the measured parameters produced virtual structures consistent with real morphologies, as confirmed by measurement of several global emergent parameters. Thus, the simple description of dendritic shape based on dendrites' tendency to grow straight, away from their own soma, and with additional random deflections, proves remarkably accurate and complete. Although based on adult neurons, these results suggest that dendritic guidance during development may be associated primarily with the host cell. This possibility challenges the traditional concept of dendritic guidance: in that hippocampal cells are densely packed and have highly overlapping dendritic fields, the somatodendritic repulsion must be cell specific. Plausible mechanisms involving extracellular effects of spikes are discussed, together with feasible experimental tests and predicted results.

Animals↗

PubMed2004

Activity-regulated cytoskeleton-associated protein Arc is targeted to dendrites and coexpressed with mu-opioid receptors in postnatal rat caudate-putamen nucleus.

Dendritic expression of the activity-regulated cytoskeleton-associated protein (Arc) is dramatically enhanced by increased synaptic activity in adult brain. We used immunocytochemical electron microscopy to determine whether the subcellular localization of Arc in developing dendrites corresponds to the peak period of synaptogenesis in the postnatal rat caudate-putamen nucleus (CPN). The distribution was compared with that of mu-opioid receptors (MORs), whose localization in dendritic spines closely parallels excitatory synapse formation during postnatal development (Wang et al. [2003] Neuroscience 118:695-708). Sections were processed for immunocytochemical detection of antisera against Arc or MORs at the beginning (postnatal day 15; P15) and the end (P30) of the peak period of synaptogenesis in rat CPN. At P15, immunolabeling for Arc showed a punctate distribution in the cytoplasm of dendritic shafts, some of which was associated with polyribosomes. In some spiny dendrites, Arc immunoreactivity was more intensely localized in putative spines than in their parental dendrites, whereas, in other spiny dendrites, Arc labeling was restricted in the shafts. Many dendritic shafts and spines also showed immunoreactivity for MORs, although dually labeled spines were less numerous than the shafts. At P30, the proportion of singly and dually labeled spines significantly increased from 2.0% to 7.5% and from 9.5% to 21%, respectively. Arc labeling in spines was more detectable beneath the postsynaptic density or at extrasynaptic sites on the plasma membrane. Our results suggest a correlation between Arc expression in dendritic spines during postnatal development and the onset of synaptogenesis in opioid-responsive neurons in the rat CPN.

Animals↗

PubMed2006

Glutamate receptor agonist kainate enhances primary dendrite number and length from immature mouse cortical neurons in vitro.

Glutamate is an important regulator of dendrite development that may inhibit, (during ischemic injury), or facilitate (during early development) dendrite growth. Previous studies have reported mainly on the N-methyl-D-aspartate (NMDA) receptor-mediated dendrite growth-promoting effect of glutamate. In this study, we examined how the non-NMDA receptor agonist kainate influenced dendrite growth. E18 mouse cortical neurons were grown for 3 days in vitro and immunolabeled with anti-microtubule-associated protein 2 (MAP2) and anti-neurofilament (NF-H), to identify dendrites and axons, respectively. Exposure of cortical neurons to kainate increased dendrite growth without affecting neuron survival. This effect was dose-dependent, reversible and blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA)/kainate receptor antagonist NBQX and the low-affinity kainate receptor antagonist NS-102, but not by the AMPA receptor antagonist CFM-2. In addition, the NMDA receptor antagonist MK-801 had no effect on kainate-induced dendrite growth. Immunolabeling and Western blot analysis of kainate receptors using antibodies against the GluR6 and KA2 subunits, demonstrated that the immature cortical neurons used in this study express kainate receptor proteins. These results suggest that kainate-induced non-NMDA receptor activation promotes dendrite growth, and in particular primary dendrite number and length, from immature cortical neurons in vitro, and that kainate receptors may be directly involved in this process. Furthermore, these data support the possibility that like NMDA receptors, kainate receptor activation may also contribute to early neurite growth from cortical neurons in vitro.

Animals↗

PubMed2006

Role of Pur alpha in targeting mRNA to sites of translation in hippocampal neuronal dendrites.

Using genetic inactivation in the mouse, PURA, encoding Pur alpha, is demonstrated to be essential for developmentally-timed dendrite formation in the cerebellum and hippocampus. Comparison of RNA species bound by Pur alpha prompts the hypothesis that Pur alpha functions with non-coding RNA in transport of certain mRNA molecules to sites of translation in dendrites. Pur alpha binds to human BC200 RNA, implicated in dendritic targeting, and this has homologies to 7SL RNA, implicated in compartmentalized translation. Results using hippocampal rat neurons in situ show that Pur alpha binds to BC1 RNA, implicated in dendritic targeting as a mouse counterpart of BC200, and to mRNA molecules translated in dendrites; Pur alpha is specifically located in dendrites, where it is colocalized with Map2, but not in axons, where it fails to colocalize with Ankyrin G. Pur alpha and Staufen are colocalized at dendritic sites of mRNA translation. Microtubule disruptors inhibit Pur alpha dendritic targeting and allow its mislocalization to axons. Using mouse brain, double-RNA immunoprecipitation places Pur alpha together with Staufen or FMRP on BC1 RNA and specific mRNA species in vivo. These results help define a mechanism by which Pur alpha targets specific mRNA molecules to sites of dendritic translation.

Animals↗

PubMed1975

A hybrid compartmental model for the alligator Purkinje cell. I: Preferred somatopetal conduction of dendritic spikes and soma-axon interaction.

A compartmental hardware model of an alligator Purkinje cell is described, consisting of a branched dendritic tree with four zones of spike generation and electrically excitable soma and initial-segment regions. Passive properties of the model compartments are represented by a cable analog circuit. Simulated action potentials, generated by a combination of depolarizing and hyperpolarizing conductance changes, are triggered in active compartments when the simulated membrane potential passes through preset thresholds. These were set at values corresponding to 28mV depolarization in the dendrites, 22 mV in the soma, and 7 mV in the initial-segment compartment. Synaptic inputs consisting of brief (0.35 msec) rectangular conductance changes give rise to exponentially decaying postsynaptic potentials in the input compartment which are electrotonically spread to other compartments. Orthodromic activation of the model neuron by computer-generated random pulse trains generates a simple spike discharge in the initial-segment compartment without evoking complex spikes. Synchronized excitatory input to the same compartments, however, does evoke a complex spike response in the soma and initial segment, coupled with dendritic spikes. Following antidromic activation of the model neuron, dendritic spikes are not generated, demonstrating a tendency in the dendritic tree for preferential conduction of spikes toward the soma. Investigation of some of the factors underlying this tendency suggests that variations in voltage attenuation due to dendritic geometry, convergence of electrotonically spread dendritic spikes, and the relative durations of dendritic and somatic action potentials may contribute to it. The presence of a threshold gradient in the dendritic tree, proposed by Llinás and his coworkers, was not found to be necessary to explain this tendency toward somatopetal conduction, although it cannot be excluded by the model. Examination of the role of the conically shaped initial-segment region suggests that this zone may provide a low-pass filter for signals conducted electrotonically from the axon to the soma, blocking repolarization of the soma during the complex spike burst generated in the axon.

Action Potentials↗

PubMed2002

Direction of action potential propagation influences calcium increases in distal dendrites of the cricket giant interneurons.

To understand the relationship between the propagation direction of action potentials and dendritic Ca(2+) elevation, simultaneous measurements of intracellular Ca(2+) concentration ([Ca(2+)](i)) and intradendritic membrane potential were performed in the wind-sensitive giant interneurons of the cricket. The dendritic Ca(2+) transients induced by synaptically-evoked action potentials had larger amplitudes than those induced by backpropagating spikes evoked by antidromic stimulation. The amplitude of the [Ca(2+)](i) changes induced by antidromic stimuli combined with subthreshold synaptic stimulation was not different from that of the Ca(2+) increases evoked by the backpropagating spikes alone. This result means that the synaptically activated Ca(2+) release from intracellular stores does not contribute to enhancement of Ca(2+) elevation induced by backpropagating spikes. On the other hand, the synaptically evoked action potentials were also increased at distal dendrites in which the Ca(2+) elevation was enhanced. When the dendritic and axonal spikes were simultaneously recorded, the delay between dendritic spike and ascending axonal spike depended upon which side of the cercal nerves was stimulated. Further, dual intracellular recording at different dendritic branches illustrated that the dendritic spike at the branch arborizing on the stimulated side preceded the spike recorded at the other side of the dendrite. These results suggest that the spike-initiation site shifts depending on the location of the activated postsynaptic site. It is proposed that the difference of spike propagation manner could change the action potential waveform at the distal dendrite, and could produce synaptic activity-dependent Ca(2+) dynamics in the giant interneurons.

Action Potentials↗

PubMed1995

Astroglia demonstrate regional differences in their ability to maintain primary dendritic outgrowth from mouse cortical neurons in vitro.

To determine whether glia from different regions of the central nervous system (CNS) initiate or maintain primary dendritic growth, embryonic day 18 mouse cortical neurons were co-cultured with rat (postnatal day 4) astroglial cells derived from retina, spinal cord, mesencephalon, striatum, olfactory bulb, retina, and cortex. Axon and dendrite outgrowth from isolated neurons was quantified using morphological and immunohistochemical techniques at 18 h and 1, 3, and 5 days in vitro. Neurons initially extend the same number of neurites, regardless of the source of glial monolayer; however, glial cells differ in their ability to maintain primary dendrites. Homotypic cortical astrocytes maintain the greatest number of primary dendrites. Glia derived from the olfactory bulb and retina maintained intermediate numbers of dendrites, whereas only a small number of primary dendrites were maintained by glia derived from striatum, spinal cord, or mesencephalon. Longer axons were initially observed from neurons grown on glia that did not maintain dendrite number. Axonal length, however, was similar on the various monolayers after 5 days in vitro. Neurons that were grown in media conditioned by either mesencephalic or cortical glia for the first 24 h followed by culture media from glia of the alternate source for 4 days in vitro confirmed that glia maintained, rather than initiated, the outgrowth of the primary dendritic arbor. These results indicate that glial cells derived from various CNS regions differ in their ability to maintain the primary dendritic arbor from mouse cortical neurons in vitro.

Animals↗

PubMed1998

Excitatory amino acid-induced degeneration of dendrites of catecholamine neurons in rat substantia nigra.

We have recently established a rat substantia nigra (SN) slice preparation in which a sensitive index of excitatory amino acid (EAA) toxicity was degeneration of the dendritic arbor of catecholamine neurons labelled by immunostaining for tyrosine hydroxylase (TH). The present study examined the pharmacological characteristics of EAA-induced neurotoxicity. Rats were anesthetised by halothane inhalation and killed, the brain was rapidly removed, and 400-microm-thick SN slices cut in the horizontal plane on a vibratome. Slices were incubated in saline buffer at 35 degreesC for 15 min to 6 h in the presence or absence or absence of kainic acid (KA) or N-methyl-D-aspartate (NMDA) in concentrations ranging from 10 to 500 microM. The slices were then fixed and resectioned into 40-microm sections that were coplanar with the parent slice. Dopaminergic SN neurons were labeled using antibody to tyrosine hydroxylase (TH) coupled to diaminobenzidine. A feature of the immunostaining was that it labeled not only the cell body but also the prolific dendritic arborization of SN neurons. Dendritic damage was quantified by counting the proportion of neurons with intact dendrites after treatment with EAA. KA and NMDA caused loss of dendrites that was prevented by CNQX (20 microM) and MK-801 (20 microM), respectively, indicating that activation of either NMDA or non-NMDA receptors produces neurotoxicity. EAA-induced dendritic damage was observed within 2 h of treatment with a low concentration (10 microM) of KA and within 15 min if the concentration was increased to 500 microM. Thus the loss of dendrites occurs rapidly and precedes disintegration of the cell bodies. Furthermore, brief (15 min) exposure to EAA initiated damage in the dendrites which progressed after the EAA was removed from its receptor. The observations are consistent with the postulated role of EAAs in neurodegenerative diseases. Labeling the dendritic arbor provides a sensitive approach to investigating the cellular mechanisms of neurodegeneration of catecholamine neurons.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1998

Distinct roles for sodium, chloride, and calcium in excitotoxic dendritic injury and recovery.

The postsynaptic neuronal dendrite is selectively vulnerable to hypoxic-ischemic brain injury and glutamate receptor overactivation. We explored the glutamate receptor pharmacology and ionic basis of rapid, reversible alterations in dendritic shape which occur in cultured neurons exposed to glutamate. Dendrite morphology was assessed with the fluorescent membrane tracer, DiI, or immunofluorescence labeling of the somatodendritic protein, MAP2. Cortical cultures derived from 15-day-old mouse embryos underwent segmental dendritic beading when exposed to NMDA, AMPA, or kainate, but not to metabotropic glutamate receptor agonists. Varicosity formation in response to NMDA or kainate application was substantially attenuated in reduced sodium buffer (substituted with N-methyl-D-glucamine). Furthermore, veratridine-induced sodium entry mimicked excitotoxic alterations in dendrites and additionally caused varicosity formation in axons. Solutions deficient in chloride (substituted with Na methylsulfate) and antagonists of chloride-permeable GABA/glycine receptors reduced NMDA- or kainate-induced varicosity formation. An increase in dendrite volume was observed as varicosities formed, and varicosity formation was attenuated in sucrose-supplemented hypertonic media. Despite marked structural changes affecting virtually all neurons, dendrite shape returned to normal within 2 h of terminating glutamate receptor agonist application. Neurons exposed to kainate recovered more rapidly than those exposed to NMDA, and neurons exposed to NMDA in calcium-free buffer recovered more rapidly than cells treated with NMDA in normal buffer. While sodium, chloride, and water entry contribute to excitotoxic dendritic injury acutely, calcium entry through NMDA receptors results in lasting structural changes in damaged dendrites.

Animals↗

PubMed1996

Rapid alterations in dendrite morphology during sublethal hypoxia or glutamate receptor activation.

Selective degeneration of postsynaptic neuronal dendrites is a pathological hallmark of brain injury in stroke and other neurological disorders. We examined dendritic injury in primary cultures dissociated from mouse neocortex. Neuronal morphology was visualized using the fluorescent membrane tracer, Dil, or immunofluorescence with antibodies to the dendrite-specific microtubule-associated protein, MAP2. Deprivation of oxygen and glucose for 30-60 min resulted in segmental dendritic beading, or varicosities, and loss of dendritic spines. This pattern of dendritic injury was blocked by addition of selective NMDA antagonists, and was reproduced within 5 min of exposure to 10-100 microM NMDA. Widespread dendritic varicosity formation occurred even with exposures to oxygen-glucose deprivation or NMDA which resulted in little neuronal death by the following day. Despite marked structural changes affecting virtually all neurons, dendrite shape returned to normal within 2 h of terminating sublethal oxygen-glucose deprivation or NMDA application. Rapid, reversible changes in dendritic structure may contribute to alterations in neuronal function following glutamate receptor stimulation under physiological or pathological conditions.

Animals↗

PubMed1997

Growth and differentiation of human dendritic cells from CD34+ progenitors.

Human dendritic cells can be generated from bone marrow CD34+ progenitors in the presence of GM-CSF and TNF alpha. The addition of a factor like c-kit-ligand optimizes the expansion of dendritic cells, as well as the other myeloid progeny grown under the same conditions, and facilitates their identification and characterization. In contrast to cord blood, where dendritic cells account for the majority of the class II MHC positive myeloid progeny, bone marrow CD34(+)-derived dendritic cells are less frequent than macrophages. When mature macrophages are depleted from days 5-6 cultures, terminally differentiated CD14+ HLA-DR dendritic cells as well as non-monocyte/macrophage CD14+ HLA-DR+ cells can be distinguished. The latter are post-CFU, bipotential, intermediate precursors that can terminally differentiate into either dendritic cells or macrophages depending on subsequent cytokine exposure. Human CD34+ progenitors isolated from bone marrow, as well as cord and peripheral blood, include CFU-DC that give rise to pure dendritic cell colonies in the combined presence of GM-CSF and TNF alpha. The different sources of CD34+ progenitors are not equivalent, however, with respect to frequency of CFU-DC growth. Cord blood is relatively enriched for dendritic cell progenitors. The developmental relationship of CFU-DC and CFU-GM, to the early developing dendritic cells and the bipotential intermediates observed in suspension culture, is not yet established.

Antigens, CD34↗

PubMed1997

Dendritic-like cells from relB mutant mice.

Mice deficient in the NF-kappa B transcription factor relB appear to have defects in the production of mature dendritic cells, as secondary lymphoid tissues are absent, and spleen cells show a significant loss of antigen presenting function. Moreover, the thymus appears to be impaired in negative selection, and immune responses in vivo are poor. Since dendritic cell precursors such as skin Langerhans cells appear to be normal, we sought information on the nature of the dendritic cell defect in these mice. Cultures of mutant bone marrow in the presence of GM-CSF revealed a delay in the accumulation of cells with dendritic cell features relative to controls; however, these cells were nearly as potent on a per cell basis as wild type cells in the stimulation of allogeneic mixed lymphocyte cultures. Similarly, skin Langerhans cells from mutant mice also showed significant ability to stimulate allogeneic T cells in culture. Since these findings cannot explain the defect in immune responses and the absence of secondary lymphoid tissues, we also looked at the ability of the relB mutant dendritic-like cells to form aggregates in vitro with naive syngeneic T cells. In this case, while wild type dendritic cells generated compact aggregates with T cells, relB mutant cells only formed irregular small aggregates. Thus, while relB mutant dendritic-like cells have some functions of mature dendritic cells, other functions are deficient. Understanding the role of relB in regulation of these functions should lead to a greater understanding of the molecular basis of dendritic cell development and function.

Animals↗