Éva Mezey - Academia.edu (original) (raw)

Papers by Éva Mezey

International Journal of Molecular Sciences

Adoptive transfer of cultured BMSCs was shown to be immune-suppressive in various inflammatory se... more Adoptive transfer of cultured BMSCs was shown to be immune-suppressive in various inflammatory settings. Many factors play a role in the process, but no master regulator of BMSC-driven immunomodulation was identified. Consequently, an assay that might predict BMSC product efficacy is still unavailable. Below, we show that BMSC donor variability can be monitored by IL-10 production of monocytes/macrophages using THP-1 cells (immortalized monocytic leukemia cells) co-cultured with BMSCs. Using a mixed lymphocyte reaction (MLR) assay, we also compared the ability of the different donor BMSCs to suppress T-cell proliferation, another measure of their immune-suppressive ability. We found that the BMSCs from a donor that induced the most IL-10 production were also the most efficient in suppressing T-cell proliferation. Transcriptome studies showed that the most potent BMSC batch also had higher expression of several known key immunomodulatory molecules such as hepatocyte growth factor (HG...

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infections result in the temporary los... more Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infections result in the temporary loss of smell and taste (anosmia and dysgeusia) in about one third of confirmed cases. Several investigators have reported that the viral spike protein receptor is present in olfactory neurons. However, no study has been published to date showing the presence of viral entry sites angiotensin-converting enzyme 2 (ACE2), neuropilin1 (NRP1), and TMPRSS2, the serine protease necessary for priming the viral proteins, in human nerves that are responsible for taste sensation (cranial nerves: VII, IX and X). We used immunocytochemistry to examine three postmortem donor samples of the IXth (glossopharyngeal) and Xth (vagal) cranial nerves where they leave/join the medulla from three donors to confirm the presence of ACE2, NRP1 and TMPRSS2. Two samples were paraffin embedded; one was a frozen sample. In addition to staining sections from the latter, we isolated RNA from it, made cDNA, and performed P...

Frontiers in Cell and Developmental Biology, 2021

Adult erythropoiesis is a highly controlled sequential differentiation of hematopoietic stem cell... more Adult erythropoiesis is a highly controlled sequential differentiation of hematopoietic stem cells (HSCs) to mature red blood cells in the bone marrow (BM). The bones which contain BM are diverse in their structure, embryonic origin, and mode of ossification. This has created substantial heterogeneity in HSCs function in BM of different bones, however, it is not known if this heterogeneity influences erythropoiesis in different bones and different regions of the same bone. In this study, we examined steady state BM erythroid progenitors and precursors from different bones – the femur, tibia, pelvis, sternum, vertebrae, radius, humerus, frontal, parietal bone, and compared all to the femur. Trabecular and cortical regions of the femur were also compared for differences in erythropoiesis. In addition, mouse spleen was studied to determine at which age erythropoietic support by the spleen was lost postnatally. We report that total erythroid cells, and erythroid precursors in the femur ...

Cytotherapy, 2018

Bone marrow derived stromal cells or mesenchymal stromal cells (BMSCs or MSCs, as we will call th... more Bone marrow derived stromal cells or mesenchymal stromal cells (BMSCs or MSCs, as we will call them in this work) are multipotent progenitor cells that can differentiate into osteoblasts, adipocytes and chondrocytes. In addition, MSCs have been shown to modulate the function of a variety of immune cells. Donor age has been shown to affect the regenerative potential, differentiation, proliferation and anti-inflammatory potency of MSCs; but the impact of donor age on their immunosuppressive activity is unknown. In this study, we evaluated the ability of MSCs derived from very young children and adults on T cell suppression and cytokine secretion by monocytes/macrophages. MSCs were obtained from extra digits of children between 10-21 months and adults between 28 and 64 years of age. We studied cell surface marker expression, doubling time, lineage differentiation potential, and immunosuppressive function of the MSCs. Young MSCs double more quickly and differentiate into bone and fat cells more efficiently than those from older donors. They also form more and dense colonies of fibroblasts (CFU-F). MSCs from both young and adult subjects suppressed T cell proliferation in a mitogen induced assay at 1:3 and 1:30 ratios. At a 1:30 ratio, however, MSCs from adults did not, but MSCs from infants did suppress T cell proliferation. In the mixed lymphocyte reaction assay, MSCs from infants produced similar levels of suppression at all three MSC/T cell ratios, but adult MSCs only inhibited T cell proliferation at a 1:3 ratio. Cytokine analyses of cocultures of MSCs and macrophages showed that both adult and young MSCs suppress TNF-α and induce IL-10 production in macrophage co-culture assay in a similar manner. Overall, this work shows that developing MSCs display a higher level of immunosuppression than mature MSCs.

Oral Diseases, 2018

ObjectiveIn women with postmenopausal osteoporosis, vitamin K2 appears to decrease the incidence ... more ObjectiveIn women with postmenopausal osteoporosis, vitamin K2 appears to decrease the incidence of hip, vertebral, and non‐vertebral fractures. Women with postmenopausal osteoporosis have more circulating activated T cells compared with healthy postmenopausal and premenopausal women, but the effects of vitamin K2 on T cells have not been studied. In this study, we have looked at T‐cell suppression by vitamin K2.Materials and methodsPeripheral blood mononuclear cells (PBMCs) from three healthy donors were used. The PBMCs were stimulated with the mitogens phytohemagglutinin and concanavalin A, and T‐cell proliferation was analyzed using flow cytometry based on carboxyfluorescein succinimidyl ester (CSFE) dye dilution.ResultsVitamin K2 (60 and 100 μM) inhibited T‐cell proliferation. Vitamin K1 at the same concentrations did not inhibit T‐cell proliferation.ConclusionVitamin K2 has immunomodulatory activities.

Cytotherapy, 2018

Background aims: Bone marrow-derived mesenchymal stromal cells (MSCs) have been reported to suppr... more Background aims: Bone marrow-derived mesenchymal stromal cells (MSCs) have been reported to suppress T-cell proliferation and used to alleviate the symptoms of graft-versus-host disease (GVHD). MSCs are a mixed cell population and at this time there are no tools to isolate the cells responsible for the T-cell suppression. We wanted to find a way to enhance the immunemodulatory actions of MSCs and tried varying the temperature at which they were cultured. Methods: We cultured human MSCs derived from healthy volunteers at different temperatures and tested their ability to switch macrophage character from pro-inflammatory to antiinflammatory (M1 type to M2 type). Using an enzyme-linked immunosorbent assay (ELISA), we showed that when MSCs are cultured at higher temperatures their ability to induce co-cultured macrophages to produce more interleukin-10, (IL-10) (an anti-inflammatory cytokine) and less tumor necrosis factor alpha, (TNFα) (a pro-inflammatory cytokine) is increased. We performed Western blots and immunocytochemistry to screen for changes that might underlie this effect. Results: We found that in hyperthermia the heat shock protein, HSF1, translocated into the nucleus of MSCs. It appears to induce the COX 2 /PGE 2 (Cyclooxygenase2/Prostaglandin E 2) pathway described earlier as a major mechanism of MSC-directed immune-suppression. Conclusion: Hyperthermia increases the efficacy of MSC-driven immune-suppression. We propose that changing the time of MSC administration to patients to mid-to-late afternoon when the body temperature is naturally highest might be beneficial. Warming the patient could also be considered.

British Journal of Dermatology, 2016

Oral Diseases, 2017

All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, m... more All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, minerals, vitamins, and water. The skeleton requires nutrients for development, maintaining bone mass and density. If the skeletal nutritional requirements are not met, the consequences can be quite severe. In recent years, there has been growing interest in promotion of bone health and inhibition of vascular calcification by vitamin K2. This vitamin regulates bone remodeling, an important process necessary to maintain adult bone. Bone remodeling involves removal of old or damaged bone by osteoclasts and its replacement by new bone formed by osteoblasts. The remodeling process is tightly regulated, when the balance between bone resorption and bone formation shifts to a net bone loss results in the development of osteoporosis in both men and women. In this review, we focus on our current understanding of the effects of vitamin K2 on bone cells and its role in prevention and treatment of os...

Catecholamines: Basic and Clinical Frontiers, 1979

Nerve terminal degenerations can be observed in different parts of the CNS thought to be involved... more Nerve terminal degenerations can be observed in different parts of the CNS thought to be involved in baroreceptor regulation, following an electrolytic lesion of the nucleus of the solitary tract (NTS) as well as transections of the medulla oblongata of the rat. These regions are: the hypothalamus, amygdala, bed nucleus of the stria terminalis (NIST). locus coeruleus (LC). Microinjection of horseradish peroxidase (HRP) into these regions resulted in an accumulation of the enzyme in the neurons of the NTS, in that part where presence of adrenaline containing perikarya has previously been shown by immunocytochemical method.

Molecular Psychiatry, 2003

A schematic illustration of the idea that a common neural progenitor (NP) gives rise to neural st... more A schematic illustration of the idea that a common neural progenitor (NP) gives rise to neural stem cells (NSCs) in the central nervous system and to neural crest stem cells (NCSCs). The NCSCs, in turn, yields two new cell populationsFone that is biased towards making neurons, and another that primarily produces glial cells in the peripheral nervous system. These two populations of cells maintain the ability to be reprogrammed by extrinsic factors. Thus, in spite of having a clear lineage commitment, NCSCs maintain some plasticity so that they can meet the needs of the organism. This paper was previously published in Volume 8 Issue 2 as black and white in error. It is reproduced here in colour.

Journal of Neuroendocrinology, 1989

We measured dopamine, norepinephrine, serotonin and epinephrine concentrations in the paraventric... more We measured dopamine, norepinephrine, serotonin and epinephrine concentrations in the paraventricular nucleus and median eminence, and corticotrophin‐releasing factor levels in the paraventricular nucleus. Tissue was isolated by micropunch technique from hypothalami of normal dogs, dogs treated for one week with dexamethasone (1 mg/kg/day) and dogs with spontaneous pituitary‐dependent hyperadrenocorticism. Concentrations of corticotrophin‐releasing factor and most of the neurotransmitters were found to be similar between our three groups of dogs. However, we found the mean dopamine concentration in the median eminence tissue to be significantly decreased in dogs with Cushing's disease and in steroid‐treated dogs. Epinephrine levels were elevated in the hypothalamic paraventricular nucleus of steroid‐treated dogs.

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2009

Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Admini... more Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Administering bone marrow stromal cells (BMSCs-also known as mesenchymal stem cells) to mice before or shortly after inducing sepsis by cecal ligation and puncture reduced mortality and improved organ function. The beneficial effect of BMSCs was eliminated by macrophage depletion or pretreatment with antibodies specific for interleukin-10 (IL-10) or IL-10 receptor. Monocytes and/ or macrophages from septic lungs made more IL-10 when prepared from mice treated with BMSCs versus untreated mice. Lipopolysaccharide (LPS)-stimulated macrophages produced more IL-10 when cultured with BMSCs, but this effect was eliminated if the BMSCs lacked the genes encoding Toll-like receptor 4, myeloid differentiation primary response gene-88, tumor necrosis factor (TNF) receptor-1a or cyclooxygenase-2. Our results suggest that BMSCs (activated by LPS or TNF-α) reprogram macrophages by releasing prostaglandin E 2 that acts on the macrophages through the prostaglandin EP2 and EP4 receptors. Because BMSCs have been successfully given to humans and can easily be cultured and might be used without human leukocyte antigen matching, we suggest that cultured, banked human BMSCs may be effective in treating sepsis in high-risk patient groups.

Stem cell research, Jan 8, 2015

Patients with systemic mastocytosis (SM) have a wide variety of problems, including skeletal abno... more Patients with systemic mastocytosis (SM) have a wide variety of problems, including skeletal abnormalities. The disease results from a mutation of the stem cell receptor (c-kit) in mast cells and we wondered if the function of bone marrow stromal cells (BMSCs; also known as MSCs or mesenchymal stem cells) might be affected by the invasion of bone marrow by mutant mast cells. As expected, BMSCs from SM patients do not have a mutation in c-kit, but they proliferate poorly. In addition, while osteogenic differentiation of the BMSCs seems to be deficient, their adipogenic potential appears to be increased. Since the hematopoietic supportive abilities of BMSCs are also important, we also studied the engraftment in NSG mice of human CD34(+) hematopoietic progenitors, after being co-cultured with BMSCs of healthy volunteers vs. BMSCs derived from patients with SM. BMSCs derived from the bone marrow of patients with SM could not support hematopoiesis to the extent that healthy BMSCs do. Fin...

Clinical Endocrinology, 2020

Dear Editor, We found Winzeler et al's paper1 on the effect of arginine vasopressin (AVP) in ... more Dear Editor, We found Winzeler et al's paper1 on the effect of arginine vasopressin (AVP) in patients suffering from central diabetes insipidus (cDI) and primary polydipsia (PP) quite interesting. They asked whether the low AVP levels in these patients were associated with anaemia. They recruited 70 cDI, 94 PP patients and 30 healthy volunteers and found that the prevalence of anaemia was low in all participants and mean haemoglobin values were similar in all groups concluding that the chronically low AVP levels in patients with cDI and PP do not affect red blood cell production. These findings contradicted our observation of lower haemoglobin/haematocrit values and an increased prevalence of anaemia in cDI patients in the United States.2 For a number of reasons, we feel that the two studies are not comparable due to the significant differences listed below:

Neuroscience Letters, 1981

Proceedings of the National Academy of Sciences, 2021

Significance The connection between brain and peripheral lymphatics has been studied for 250 y, m... more Significance The connection between brain and peripheral lymphatics has been studied for 250 y, mainly in animals. Specific markers for lymphatic endothelial cells (LECs) were discovered about a decade ago. We stained postmortem human brains with LYVE1 and PDPN to identify LECs. Marker-positive cells were found in membranes covering the brain, walls of vessels, and perivascular spaces, and among nerve fibers. These spaces also seem to contain T cells and are connected to peripheral lymphatics through passageways in the nasal cavity, optic nerve, and base of the skull. Our findings show a path that brain waste products take when they leave the central nervous system, paths that may be bidirectional.

Cancers

Melanoma-associated fibroblasts (MAFs) are integral parts of melanoma, providing a protective net... more Melanoma-associated fibroblasts (MAFs) are integral parts of melanoma, providing a protective network for melanoma cells. The phenotypical and functional similarities between MAFs and mesenchymal stromal cells (MSCs) prompted us to investigate if, similarly to MSCs, MAFs are capable of modulating macrophage functions. Using immunohistochemistry, we showed that MAFs and macrophages are in intimate contact within the tumor stroma. We then demonstrated that MAFs indeed are potent inducers of IL-10 production in various macrophage types in vitro, and this process is greatly augmented by the presence of treatment-naïve and chemotherapy-treated melanoma cells. MAFs derived from thick melanomas appear to be more immunosuppressive than those cultured from thin melanomas. The IL-10 increasing effect is mediated, at least in part, by cyclooxygenase and indoleamine 2,3-dioxygenase. Our data indicate that MAF-induced IL-10 production in macrophages may contribute to melanoma aggressiveness, and...

Stem Cells Translational Medicine, 2022

Studies of mesenchymal stem (or stromal) cells (MSCs) have moved from bedside to bench and back a... more Studies of mesenchymal stem (or stromal) cells (MSCs) have moved from bedside to bench and back again. The stromal cells or fibroblasts are found in all tissues and participate in building the extracellular matrix (ECM). Bone marrow (BM)-derived MSCs have been studied for more than 50 years and have multiple roles. They function as stem cells and give rise to bone, cartilage, and fat in the BM (these are stem cells); support hematopoiesis (pericytes); and participate in sensing environmental changes and balancing pro- and anti-inflammatory conditions. In disease states, they migrate to sites of injury and release cytokines, hormones, nucleic acids depending on the microenvironment they find. Clinicians have begun to exploit these properties of BM, adipose tissue, and umbilical cord MSCs because they are easy to harvest and expand in culture. In this review, I describe the uses to which MSCs have been put, list ongoing clinical trials by organ system, and outline how MSCs are thought...

International Journal of Molecular Sciences

Adoptive transfer of cultured BMSCs was shown to be immune-suppressive in various inflammatory se... more Adoptive transfer of cultured BMSCs was shown to be immune-suppressive in various inflammatory settings. Many factors play a role in the process, but no master regulator of BMSC-driven immunomodulation was identified. Consequently, an assay that might predict BMSC product efficacy is still unavailable. Below, we show that BMSC donor variability can be monitored by IL-10 production of monocytes/macrophages using THP-1 cells (immortalized monocytic leukemia cells) co-cultured with BMSCs. Using a mixed lymphocyte reaction (MLR) assay, we also compared the ability of the different donor BMSCs to suppress T-cell proliferation, another measure of their immune-suppressive ability. We found that the BMSCs from a donor that induced the most IL-10 production were also the most efficient in suppressing T-cell proliferation. Transcriptome studies showed that the most potent BMSC batch also had higher expression of several known key immunomodulatory molecules such as hepatocyte growth factor (HG...

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infections result in the temporary los... more Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infections result in the temporary loss of smell and taste (anosmia and dysgeusia) in about one third of confirmed cases. Several investigators have reported that the viral spike protein receptor is present in olfactory neurons. However, no study has been published to date showing the presence of viral entry sites angiotensin-converting enzyme 2 (ACE2), neuropilin1 (NRP1), and TMPRSS2, the serine protease necessary for priming the viral proteins, in human nerves that are responsible for taste sensation (cranial nerves: VII, IX and X). We used immunocytochemistry to examine three postmortem donor samples of the IXth (glossopharyngeal) and Xth (vagal) cranial nerves where they leave/join the medulla from three donors to confirm the presence of ACE2, NRP1 and TMPRSS2. Two samples were paraffin embedded; one was a frozen sample. In addition to staining sections from the latter, we isolated RNA from it, made cDNA, and performed P...

Frontiers in Cell and Developmental Biology, 2021

Adult erythropoiesis is a highly controlled sequential differentiation of hematopoietic stem cell... more Adult erythropoiesis is a highly controlled sequential differentiation of hematopoietic stem cells (HSCs) to mature red blood cells in the bone marrow (BM). The bones which contain BM are diverse in their structure, embryonic origin, and mode of ossification. This has created substantial heterogeneity in HSCs function in BM of different bones, however, it is not known if this heterogeneity influences erythropoiesis in different bones and different regions of the same bone. In this study, we examined steady state BM erythroid progenitors and precursors from different bones – the femur, tibia, pelvis, sternum, vertebrae, radius, humerus, frontal, parietal bone, and compared all to the femur. Trabecular and cortical regions of the femur were also compared for differences in erythropoiesis. In addition, mouse spleen was studied to determine at which age erythropoietic support by the spleen was lost postnatally. We report that total erythroid cells, and erythroid precursors in the femur ...

Cytotherapy, 2018

Bone marrow derived stromal cells or mesenchymal stromal cells (BMSCs or MSCs, as we will call th... more Bone marrow derived stromal cells or mesenchymal stromal cells (BMSCs or MSCs, as we will call them in this work) are multipotent progenitor cells that can differentiate into osteoblasts, adipocytes and chondrocytes. In addition, MSCs have been shown to modulate the function of a variety of immune cells. Donor age has been shown to affect the regenerative potential, differentiation, proliferation and anti-inflammatory potency of MSCs; but the impact of donor age on their immunosuppressive activity is unknown. In this study, we evaluated the ability of MSCs derived from very young children and adults on T cell suppression and cytokine secretion by monocytes/macrophages. MSCs were obtained from extra digits of children between 10-21 months and adults between 28 and 64 years of age. We studied cell surface marker expression, doubling time, lineage differentiation potential, and immunosuppressive function of the MSCs. Young MSCs double more quickly and differentiate into bone and fat cells more efficiently than those from older donors. They also form more and dense colonies of fibroblasts (CFU-F). MSCs from both young and adult subjects suppressed T cell proliferation in a mitogen induced assay at 1:3 and 1:30 ratios. At a 1:30 ratio, however, MSCs from adults did not, but MSCs from infants did suppress T cell proliferation. In the mixed lymphocyte reaction assay, MSCs from infants produced similar levels of suppression at all three MSC/T cell ratios, but adult MSCs only inhibited T cell proliferation at a 1:3 ratio. Cytokine analyses of cocultures of MSCs and macrophages showed that both adult and young MSCs suppress TNF-α and induce IL-10 production in macrophage co-culture assay in a similar manner. Overall, this work shows that developing MSCs display a higher level of immunosuppression than mature MSCs.

Oral Diseases, 2018

ObjectiveIn women with postmenopausal osteoporosis, vitamin K2 appears to decrease the incidence ... more ObjectiveIn women with postmenopausal osteoporosis, vitamin K2 appears to decrease the incidence of hip, vertebral, and non‐vertebral fractures. Women with postmenopausal osteoporosis have more circulating activated T cells compared with healthy postmenopausal and premenopausal women, but the effects of vitamin K2 on T cells have not been studied. In this study, we have looked at T‐cell suppression by vitamin K2.Materials and methodsPeripheral blood mononuclear cells (PBMCs) from three healthy donors were used. The PBMCs were stimulated with the mitogens phytohemagglutinin and concanavalin A, and T‐cell proliferation was analyzed using flow cytometry based on carboxyfluorescein succinimidyl ester (CSFE) dye dilution.ResultsVitamin K2 (60 and 100 μM) inhibited T‐cell proliferation. Vitamin K1 at the same concentrations did not inhibit T‐cell proliferation.ConclusionVitamin K2 has immunomodulatory activities.

Cytotherapy, 2018

Background aims: Bone marrow-derived mesenchymal stromal cells (MSCs) have been reported to suppr... more Background aims: Bone marrow-derived mesenchymal stromal cells (MSCs) have been reported to suppress T-cell proliferation and used to alleviate the symptoms of graft-versus-host disease (GVHD). MSCs are a mixed cell population and at this time there are no tools to isolate the cells responsible for the T-cell suppression. We wanted to find a way to enhance the immunemodulatory actions of MSCs and tried varying the temperature at which they were cultured. Methods: We cultured human MSCs derived from healthy volunteers at different temperatures and tested their ability to switch macrophage character from pro-inflammatory to antiinflammatory (M1 type to M2 type). Using an enzyme-linked immunosorbent assay (ELISA), we showed that when MSCs are cultured at higher temperatures their ability to induce co-cultured macrophages to produce more interleukin-10, (IL-10) (an anti-inflammatory cytokine) and less tumor necrosis factor alpha, (TNFα) (a pro-inflammatory cytokine) is increased. We performed Western blots and immunocytochemistry to screen for changes that might underlie this effect. Results: We found that in hyperthermia the heat shock protein, HSF1, translocated into the nucleus of MSCs. It appears to induce the COX 2 /PGE 2 (Cyclooxygenase2/Prostaglandin E 2) pathway described earlier as a major mechanism of MSC-directed immune-suppression. Conclusion: Hyperthermia increases the efficacy of MSC-driven immune-suppression. We propose that changing the time of MSC administration to patients to mid-to-late afternoon when the body temperature is naturally highest might be beneficial. Warming the patient could also be considered.

British Journal of Dermatology, 2016

Oral Diseases, 2017

All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, m... more All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, minerals, vitamins, and water. The skeleton requires nutrients for development, maintaining bone mass and density. If the skeletal nutritional requirements are not met, the consequences can be quite severe. In recent years, there has been growing interest in promotion of bone health and inhibition of vascular calcification by vitamin K2. This vitamin regulates bone remodeling, an important process necessary to maintain adult bone. Bone remodeling involves removal of old or damaged bone by osteoclasts and its replacement by new bone formed by osteoblasts. The remodeling process is tightly regulated, when the balance between bone resorption and bone formation shifts to a net bone loss results in the development of osteoporosis in both men and women. In this review, we focus on our current understanding of the effects of vitamin K2 on bone cells and its role in prevention and treatment of os...

Catecholamines: Basic and Clinical Frontiers, 1979

Nerve terminal degenerations can be observed in different parts of the CNS thought to be involved... more Nerve terminal degenerations can be observed in different parts of the CNS thought to be involved in baroreceptor regulation, following an electrolytic lesion of the nucleus of the solitary tract (NTS) as well as transections of the medulla oblongata of the rat. These regions are: the hypothalamus, amygdala, bed nucleus of the stria terminalis (NIST). locus coeruleus (LC). Microinjection of horseradish peroxidase (HRP) into these regions resulted in an accumulation of the enzyme in the neurons of the NTS, in that part where presence of adrenaline containing perikarya has previously been shown by immunocytochemical method.

Molecular Psychiatry, 2003

A schematic illustration of the idea that a common neural progenitor (NP) gives rise to neural st... more A schematic illustration of the idea that a common neural progenitor (NP) gives rise to neural stem cells (NSCs) in the central nervous system and to neural crest stem cells (NCSCs). The NCSCs, in turn, yields two new cell populationsFone that is biased towards making neurons, and another that primarily produces glial cells in the peripheral nervous system. These two populations of cells maintain the ability to be reprogrammed by extrinsic factors. Thus, in spite of having a clear lineage commitment, NCSCs maintain some plasticity so that they can meet the needs of the organism. This paper was previously published in Volume 8 Issue 2 as black and white in error. It is reproduced here in colour.

Journal of Neuroendocrinology, 1989

We measured dopamine, norepinephrine, serotonin and epinephrine concentrations in the paraventric... more We measured dopamine, norepinephrine, serotonin and epinephrine concentrations in the paraventricular nucleus and median eminence, and corticotrophin‐releasing factor levels in the paraventricular nucleus. Tissue was isolated by micropunch technique from hypothalami of normal dogs, dogs treated for one week with dexamethasone (1 mg/kg/day) and dogs with spontaneous pituitary‐dependent hyperadrenocorticism. Concentrations of corticotrophin‐releasing factor and most of the neurotransmitters were found to be similar between our three groups of dogs. However, we found the mean dopamine concentration in the median eminence tissue to be significantly decreased in dogs with Cushing's disease and in steroid‐treated dogs. Epinephrine levels were elevated in the hypothalamic paraventricular nucleus of steroid‐treated dogs.

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2009

Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Admini... more Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Administering bone marrow stromal cells (BMSCs-also known as mesenchymal stem cells) to mice before or shortly after inducing sepsis by cecal ligation and puncture reduced mortality and improved organ function. The beneficial effect of BMSCs was eliminated by macrophage depletion or pretreatment with antibodies specific for interleukin-10 (IL-10) or IL-10 receptor. Monocytes and/ or macrophages from septic lungs made more IL-10 when prepared from mice treated with BMSCs versus untreated mice. Lipopolysaccharide (LPS)-stimulated macrophages produced more IL-10 when cultured with BMSCs, but this effect was eliminated if the BMSCs lacked the genes encoding Toll-like receptor 4, myeloid differentiation primary response gene-88, tumor necrosis factor (TNF) receptor-1a or cyclooxygenase-2. Our results suggest that BMSCs (activated by LPS or TNF-α) reprogram macrophages by releasing prostaglandin E 2 that acts on the macrophages through the prostaglandin EP2 and EP4 receptors. Because BMSCs have been successfully given to humans and can easily be cultured and might be used without human leukocyte antigen matching, we suggest that cultured, banked human BMSCs may be effective in treating sepsis in high-risk patient groups.

Stem cell research, Jan 8, 2015

Patients with systemic mastocytosis (SM) have a wide variety of problems, including skeletal abno... more Patients with systemic mastocytosis (SM) have a wide variety of problems, including skeletal abnormalities. The disease results from a mutation of the stem cell receptor (c-kit) in mast cells and we wondered if the function of bone marrow stromal cells (BMSCs; also known as MSCs or mesenchymal stem cells) might be affected by the invasion of bone marrow by mutant mast cells. As expected, BMSCs from SM patients do not have a mutation in c-kit, but they proliferate poorly. In addition, while osteogenic differentiation of the BMSCs seems to be deficient, their adipogenic potential appears to be increased. Since the hematopoietic supportive abilities of BMSCs are also important, we also studied the engraftment in NSG mice of human CD34(+) hematopoietic progenitors, after being co-cultured with BMSCs of healthy volunteers vs. BMSCs derived from patients with SM. BMSCs derived from the bone marrow of patients with SM could not support hematopoiesis to the extent that healthy BMSCs do. Fin...

Clinical Endocrinology, 2020

Dear Editor, We found Winzeler et al's paper1 on the effect of arginine vasopressin (AVP) in ... more Dear Editor, We found Winzeler et al's paper1 on the effect of arginine vasopressin (AVP) in patients suffering from central diabetes insipidus (cDI) and primary polydipsia (PP) quite interesting. They asked whether the low AVP levels in these patients were associated with anaemia. They recruited 70 cDI, 94 PP patients and 30 healthy volunteers and found that the prevalence of anaemia was low in all participants and mean haemoglobin values were similar in all groups concluding that the chronically low AVP levels in patients with cDI and PP do not affect red blood cell production. These findings contradicted our observation of lower haemoglobin/haematocrit values and an increased prevalence of anaemia in cDI patients in the United States.2 For a number of reasons, we feel that the two studies are not comparable due to the significant differences listed below:

Neuroscience Letters, 1981

Proceedings of the National Academy of Sciences, 2021

Significance The connection between brain and peripheral lymphatics has been studied for 250 y, m... more Significance The connection between brain and peripheral lymphatics has been studied for 250 y, mainly in animals. Specific markers for lymphatic endothelial cells (LECs) were discovered about a decade ago. We stained postmortem human brains with LYVE1 and PDPN to identify LECs. Marker-positive cells were found in membranes covering the brain, walls of vessels, and perivascular spaces, and among nerve fibers. These spaces also seem to contain T cells and are connected to peripheral lymphatics through passageways in the nasal cavity, optic nerve, and base of the skull. Our findings show a path that brain waste products take when they leave the central nervous system, paths that may be bidirectional.

Cancers

Melanoma-associated fibroblasts (MAFs) are integral parts of melanoma, providing a protective net... more Melanoma-associated fibroblasts (MAFs) are integral parts of melanoma, providing a protective network for melanoma cells. The phenotypical and functional similarities between MAFs and mesenchymal stromal cells (MSCs) prompted us to investigate if, similarly to MSCs, MAFs are capable of modulating macrophage functions. Using immunohistochemistry, we showed that MAFs and macrophages are in intimate contact within the tumor stroma. We then demonstrated that MAFs indeed are potent inducers of IL-10 production in various macrophage types in vitro, and this process is greatly augmented by the presence of treatment-naïve and chemotherapy-treated melanoma cells. MAFs derived from thick melanomas appear to be more immunosuppressive than those cultured from thin melanomas. The IL-10 increasing effect is mediated, at least in part, by cyclooxygenase and indoleamine 2,3-dioxygenase. Our data indicate that MAF-induced IL-10 production in macrophages may contribute to melanoma aggressiveness, and...

Stem Cells Translational Medicine, 2022

Studies of mesenchymal stem (or stromal) cells (MSCs) have moved from bedside to bench and back a... more Studies of mesenchymal stem (or stromal) cells (MSCs) have moved from bedside to bench and back again. The stromal cells or fibroblasts are found in all tissues and participate in building the extracellular matrix (ECM). Bone marrow (BM)-derived MSCs have been studied for more than 50 years and have multiple roles. They function as stem cells and give rise to bone, cartilage, and fat in the BM (these are stem cells); support hematopoiesis (pericytes); and participate in sensing environmental changes and balancing pro- and anti-inflammatory conditions. In disease states, they migrate to sites of injury and release cytokines, hormones, nucleic acids depending on the microenvironment they find. Clinicians have begun to exploit these properties of BM, adipose tissue, and umbilical cord MSCs because they are easy to harvest and expand in culture. In this review, I describe the uses to which MSCs have been put, list ongoing clinical trials by organ system, and outline how MSCs are thought...