Journal of the American Society of Nephrology, 2007
Wnt proteins are required for induction of nephrons in mouse metanephric kidneys, but the downstr... more Wnt proteins are required for induction of nephrons in mouse metanephric kidneys, but the downstream pathways that mediate tubule induction and epithelial differentiation have remained obscure. The intracellular mechanisms by which Wnt signaling mediates nephron induction in embryonic kidney mesenchymes were studied. First is shown that transient exposure of isolated kidney mesenchymes to structurally different glycogen synthase kinase-3 (GSK3) inhibitors lithium or 6-bromoindirubin-3-oxime results in abundant epithelial differentiation and full segregation of nephrons. Shown further by mice with genetically disrupted ureteric bud or Wolffian duct development is that this nephrogenic competence arises independent of the influence of Wolffian duct-derived epithelia. Analysis of the intracellular signaling cascades downstream of GSK3 inhibition revealed stabilization of -catenin and upregulation of Lef1 and Tcf1, both events that are associated with the active canonical Wnt signaling. Last, genetic evidence that metanephric mesenchyme-specific stabilization of -catenin is sufficient to induce nephron differentiation in isolated kidney mesenchymes, similar to that induced by GSK3 inhibitors, is provided. These data show that activation of canonical Wnt pathway is sufficient to induce nephrogenesis and suggest that this pathway mediates the nephron induction in murine kidney mesenchymes.
We show with transgenic mice that targeted overexpression of glial cell line-derived neurotrophic... more We show with transgenic mice that targeted overexpression of glial cell line-derived neurotrophic factor (GDNF) in undifferentiated spermatogonia promotes malignant testicular tumors, which express germ-cell markers. The tumors are invasive and contain aneuploid cells, but no distant metastases have been found. By several histological, molecular, and histochemical characteristics, the GDNF-induced tumors mimic classic seminomas in men, representing a useful experimental model for testicular germ-cell tumors. The data also show that a deregulated stimulation of a normal proto-oncogene by its ligand can be an initiative event in carcinogenesis.
The central nervous system (CNS) harbors multiple glial fibrillary acidic protein (GFAP) expressi... more The central nervous system (CNS) harbors multiple glial fibrillary acidic protein (GFAP) expressing cell types. In addition to the most abundant cell type of the CNS, the astrocytes, various stem cells and progenitor cells also contain GFAP+ populations. Here, in order to distinguish between two types of GFAP expressing cells with or without the expression of the A2B5 antigens, we performed lipidomic analyses on A2B5+/GFAP+ and A2B5-/GFAP+ cells from rat spinal cord. First, A2B5+/GFAP- progenitors were exposed to the leukemia inhibitory factor (LIF) or bone morphogenetic protein (BMP) to induce their differentiation to A2B5+/GFAP+ cells or A2B5-/GFAP+ astrocytes, respectively. The cells were then analyzed for changes in their phospholipid, sphingolipid or acyl chain profiles by mass spectrometry and gas chromatography. Compared to A2B5+/GFAP- progenitors, A2B5-/GFAP+ astrocytes contained higher amounts of ether phospholipids (especially the species containing arachidonic acid) and s...
Most studies on the growth of vessels have so far focused on the tumour vascularization or that o... more Most studies on the growth of vessels have so far focused on the tumour vascularization or that occurring in the area of inflammation. The mechanisms of embryonic angiogenesis have not been characterized in such a detail and only relatively few experimental studies have been carried out to analyse the origin and development of the embryonic vasculature. It is not known if the vessels develop in situ in each organ rudiment or by invasion of earlier committed vascular cells. Because morphological analyses of in vivo tissues have proved to be unreliable for judging the origin of vascular cells, new methods have been presented. Nuclear differences between of some species can be used to trace the origin of cells in interspecies transplantation experiments. This review presents data on the biology of vasculogenesis and shows how interspecies chimeras can be used in studies on angiogenesis. For example, the transplantation experiments with embryonic kidneys are described in more detail.
The International journal of developmental biology, 1994
The metanephric mesenchyme is considered a homogeneous population of predetermined, but pluripote... more The metanephric mesenchyme is considered a homogeneous population of predetermined, but pluripotent cells with a nephrogenic bias. By an inductive stimulus, the mesenchyme is programmed to differentiate into the various epithelial phenotypes of the secretory nephron. A fraction of the mesenchymal cells, however, remains in the interstitium between the nephrons and differentiates into spindle-shaped, clear-cytoplasmic renal stroma. We have analyzed the molecular nature of these cells in order to discover the specific cell types that could be involved in the morphogenetic processes during kidney differentiation. In situ hybridization reveals neurofilament light protein mRNA, and immunohistology shows neurofilament light and medium proteins in the stromal cells around kidney tubules. By immunohistochemistry these peritubular stromal cells can be distinguished from the neuronal cells of the renal microganglion: the peritubular stromal cells are neurofilament-positive but L1 neural cell ...
The migration of capillaries into mouse embryonic kidneys grafted on quail chorioallantoic membra... more The migration of capillaries into mouse embryonic kidneys grafted on quail chorioallantoic membrane (CAM) was analyzed by two monoclonal antibodies against quail endothelial and haematopoietic cells. As shown by immunohistochemistry, the quail chorioallantoic vessels invaded the kidney explant. Initially, the capillaries were detected in the interstitial stroma and, soon thereafter, tightly adjacent to the branches of the ureteric bud. The induced mesenchymal cell condensates, the prospective nephric vesicles, were avascular, but when the early S-shaped body was formed, the capillaries invaded its lower crevice. Finally chimeric glomeruli consisting of mouse podocytes and quail endothelial cells, were formed and, contemporarily, the capillaries ceased to migrate. Within the endothelial-mesangial area of the chimeric glomeruli, all cells expressed the quail-type nuclear structure and were stained by the quail endothelial-specific antibodies. The pattern of migrating capillaries was c...
Avascular, undifferentiated mouse kidneys transplanted onto quail chorioallantoic membrane differ... more Avascular, undifferentiated mouse kidneys transplanted onto quail chorioallantoic membrane differentiate and become vascularized by quail vessels. The glomeruli which form under these conditions consist of mouse podocytes and quail endothelial cells. Immunohistochemistry has shown that the glomerular basement membrane (GBM) has a dual origin, as integral basement membrane components are produced by both podocytes and endothelial cells. In electron microscopy this GBM is composed of two partially separated layers, an epithelial and an endothelial basal lamina which both have a lamina densa and a lamina rara. These two basal laminas are partially fused, but there are large areas where this fusion does not occur. In some places of incomplete fusion, fibrillar extracellular material is seen between and beneath the GBM. It is concluded that basement membrane components derived from the different species can interact partially, but the fusion is incomplete. The abnormal assembly of the ep...
The origin of the glomerular endothelium has remained unsettled, although it has mostly been assu... more The origin of the glomerular endothelium has remained unsettled, although it has mostly been assumed that it is derived from the metanephric mesenchyrne, like,the other parts of the nephron. Since our recent observations did not support this concept, the development of the vasculature of the kidney aud of the glomerular endothelium was studied using both mouse/quail and quail/chick interspecies grafts. Undifferentiated ll-day mouse kidney anlagen were transplanted onto quail chorioallantoic membrane and allowed to develop for 7-10 days. Upon examination, grafts were well-vascularized, and both the glomarular and the vessel endothelium expressed the quail nuclear marker. Similar results were obtained in quail/chick transplantation experiments. Hence, we suggest that the endothelium of the glomeruli is derived from outside vasculature rather than by conversion of cells in the nephrogenic masenchyme. interspecies transplantation kidney development vascularization
The cellular origin of fibronectin in the kidney was studied in three experimental models. Immuno... more The cellular origin of fibronectin in the kidney was studied in three experimental models. Immunohistochemical techniques that use cross-reacting or species-specific antibodies against mouse or chicken fibronectin were employed. In the first model studied, initially avascular mouse kidneys cultured on avian chorioallantoic membranes differentiate into epithelial kidney tubules and become vascularized by chorioallantoic vessels. Subsequently, hybrid glomeruli composed of mouse podocytes and avian endothelial-mesangial cells form. In immunohistochemical studies, cross-reacting antibodies to fibronectin stained vascular walls, tubular basement membranes, interstitium, and glomeruli of mouse kidney grafts. The species-specific antibodies reacting only with mouse fibronectin stained interstitial areas and tubular basement membranes, but showed no reaction with hybrid glomeruli and avian vascular walls. In contrast, species-specific antibodies against chicken fibronectin stained both the ...
Scandinavian Journal of Thoracic and Cardiovascular Surgery, 1986
During the years 1964-82 a total of 60 patients underwent surgery for aortic dissection. Forty of... more During the years 1964-82 a total of 60 patients underwent surgery for aortic dissection. Forty of them were males, with a mean age of 48.8 years (22 to 69) and 20 were females, with a mean age of 49.0 years (31 to 65). Forty-five patients were operated in an acute stage of aortic dissection and 15 patients in a chronic stage of this disease. The mortality rate of patients operated on for acute dissections was 51.1% and of patients with a chronic dissection 13.3%, the over-all hospital mortality rate being 41.7%. Cardiac and haemorrhagic complications were the commonest cause of death. Among the 35 operative survivors, there were seven late deaths (11.7%); 4 patients died of cardiovascular causes. The mean follow-up time was 6.1 years (2.7 to 13.4). Twenty-six long-term survivors were re-examined in the hospital.
Proceedings of the National Academy of Sciences, 1995
We analyzed the developmental regulation and role of the neurotrophins during metanephric kidney ... more We analyzed the developmental regulation and role of the neurotrophins during metanephric kidney morphogenesis. RNase protection assay revealed the presence of nerve growth factor, neurotrophin 3 (NT-3), and brainderived neurotrophic factor mRNAs and the regulation of their expression during embryonic development of rat metanephros. NT-3 induced differentiation (neurite outgrowth) and survival (inhibition of apoptosis) of the neuronal precursors in cultured nephrogenic mesenchymes and neuronal differentiation in cultured whole kidneys, whereas NT-4/5,
Two cases of breast tumors with a uniform solid carcinoid pattern and argyrophilic dense-core gra... more Two cases of breast tumors with a uniform solid carcinoid pattern and argyrophilic dense-core granules were analyzed by immunohistochemistry in order to compare their characteristics with known features of other carcinoid tumors and ordinary breast carcinomas. The tumors were positive for keratin-type intermediate filaments, neuron-specific enolase and alpha-chain of human chorion gonadotropin but negative for vimentin and S-100 protein. Laminin was found only in a rim between tumor cell islands and stroma but not among the cells. It is concluded that these tumors are histologically, ultrastructurally and immunohistochemically similar to other carcinoid tumors. The present results suggest that both breast carcinoids and carcinomas may have a common precursor in the mammary secretory unit.
Journal of the American Society of Nephrology, 2007
Wnt proteins are required for induction of nephrons in mouse metanephric kidneys, but the downstr... more Wnt proteins are required for induction of nephrons in mouse metanephric kidneys, but the downstream pathways that mediate tubule induction and epithelial differentiation have remained obscure. The intracellular mechanisms by which Wnt signaling mediates nephron induction in embryonic kidney mesenchymes were studied. First is shown that transient exposure of isolated kidney mesenchymes to structurally different glycogen synthase kinase-3 (GSK3) inhibitors lithium or 6-bromoindirubin-3-oxime results in abundant epithelial differentiation and full segregation of nephrons. Shown further by mice with genetically disrupted ureteric bud or Wolffian duct development is that this nephrogenic competence arises independent of the influence of Wolffian duct-derived epithelia. Analysis of the intracellular signaling cascades downstream of GSK3 inhibition revealed stabilization of -catenin and upregulation of Lef1 and Tcf1, both events that are associated with the active canonical Wnt signaling. Last, genetic evidence that metanephric mesenchyme-specific stabilization of -catenin is sufficient to induce nephron differentiation in isolated kidney mesenchymes, similar to that induced by GSK3 inhibitors, is provided. These data show that activation of canonical Wnt pathway is sufficient to induce nephrogenesis and suggest that this pathway mediates the nephron induction in murine kidney mesenchymes.
We show with transgenic mice that targeted overexpression of glial cell line-derived neurotrophic... more We show with transgenic mice that targeted overexpression of glial cell line-derived neurotrophic factor (GDNF) in undifferentiated spermatogonia promotes malignant testicular tumors, which express germ-cell markers. The tumors are invasive and contain aneuploid cells, but no distant metastases have been found. By several histological, molecular, and histochemical characteristics, the GDNF-induced tumors mimic classic seminomas in men, representing a useful experimental model for testicular germ-cell tumors. The data also show that a deregulated stimulation of a normal proto-oncogene by its ligand can be an initiative event in carcinogenesis.
The central nervous system (CNS) harbors multiple glial fibrillary acidic protein (GFAP) expressi... more The central nervous system (CNS) harbors multiple glial fibrillary acidic protein (GFAP) expressing cell types. In addition to the most abundant cell type of the CNS, the astrocytes, various stem cells and progenitor cells also contain GFAP+ populations. Here, in order to distinguish between two types of GFAP expressing cells with or without the expression of the A2B5 antigens, we performed lipidomic analyses on A2B5+/GFAP+ and A2B5-/GFAP+ cells from rat spinal cord. First, A2B5+/GFAP- progenitors were exposed to the leukemia inhibitory factor (LIF) or bone morphogenetic protein (BMP) to induce their differentiation to A2B5+/GFAP+ cells or A2B5-/GFAP+ astrocytes, respectively. The cells were then analyzed for changes in their phospholipid, sphingolipid or acyl chain profiles by mass spectrometry and gas chromatography. Compared to A2B5+/GFAP- progenitors, A2B5-/GFAP+ astrocytes contained higher amounts of ether phospholipids (especially the species containing arachidonic acid) and s...
Most studies on the growth of vessels have so far focused on the tumour vascularization or that o... more Most studies on the growth of vessels have so far focused on the tumour vascularization or that occurring in the area of inflammation. The mechanisms of embryonic angiogenesis have not been characterized in such a detail and only relatively few experimental studies have been carried out to analyse the origin and development of the embryonic vasculature. It is not known if the vessels develop in situ in each organ rudiment or by invasion of earlier committed vascular cells. Because morphological analyses of in vivo tissues have proved to be unreliable for judging the origin of vascular cells, new methods have been presented. Nuclear differences between of some species can be used to trace the origin of cells in interspecies transplantation experiments. This review presents data on the biology of vasculogenesis and shows how interspecies chimeras can be used in studies on angiogenesis. For example, the transplantation experiments with embryonic kidneys are described in more detail.
The International journal of developmental biology, 1994
The metanephric mesenchyme is considered a homogeneous population of predetermined, but pluripote... more The metanephric mesenchyme is considered a homogeneous population of predetermined, but pluripotent cells with a nephrogenic bias. By an inductive stimulus, the mesenchyme is programmed to differentiate into the various epithelial phenotypes of the secretory nephron. A fraction of the mesenchymal cells, however, remains in the interstitium between the nephrons and differentiates into spindle-shaped, clear-cytoplasmic renal stroma. We have analyzed the molecular nature of these cells in order to discover the specific cell types that could be involved in the morphogenetic processes during kidney differentiation. In situ hybridization reveals neurofilament light protein mRNA, and immunohistology shows neurofilament light and medium proteins in the stromal cells around kidney tubules. By immunohistochemistry these peritubular stromal cells can be distinguished from the neuronal cells of the renal microganglion: the peritubular stromal cells are neurofilament-positive but L1 neural cell ...
The migration of capillaries into mouse embryonic kidneys grafted on quail chorioallantoic membra... more The migration of capillaries into mouse embryonic kidneys grafted on quail chorioallantoic membrane (CAM) was analyzed by two monoclonal antibodies against quail endothelial and haematopoietic cells. As shown by immunohistochemistry, the quail chorioallantoic vessels invaded the kidney explant. Initially, the capillaries were detected in the interstitial stroma and, soon thereafter, tightly adjacent to the branches of the ureteric bud. The induced mesenchymal cell condensates, the prospective nephric vesicles, were avascular, but when the early S-shaped body was formed, the capillaries invaded its lower crevice. Finally chimeric glomeruli consisting of mouse podocytes and quail endothelial cells, were formed and, contemporarily, the capillaries ceased to migrate. Within the endothelial-mesangial area of the chimeric glomeruli, all cells expressed the quail-type nuclear structure and were stained by the quail endothelial-specific antibodies. The pattern of migrating capillaries was c...
Avascular, undifferentiated mouse kidneys transplanted onto quail chorioallantoic membrane differ... more Avascular, undifferentiated mouse kidneys transplanted onto quail chorioallantoic membrane differentiate and become vascularized by quail vessels. The glomeruli which form under these conditions consist of mouse podocytes and quail endothelial cells. Immunohistochemistry has shown that the glomerular basement membrane (GBM) has a dual origin, as integral basement membrane components are produced by both podocytes and endothelial cells. In electron microscopy this GBM is composed of two partially separated layers, an epithelial and an endothelial basal lamina which both have a lamina densa and a lamina rara. These two basal laminas are partially fused, but there are large areas where this fusion does not occur. In some places of incomplete fusion, fibrillar extracellular material is seen between and beneath the GBM. It is concluded that basement membrane components derived from the different species can interact partially, but the fusion is incomplete. The abnormal assembly of the ep...
The origin of the glomerular endothelium has remained unsettled, although it has mostly been assu... more The origin of the glomerular endothelium has remained unsettled, although it has mostly been assumed that it is derived from the metanephric mesenchyrne, like,the other parts of the nephron. Since our recent observations did not support this concept, the development of the vasculature of the kidney aud of the glomerular endothelium was studied using both mouse/quail and quail/chick interspecies grafts. Undifferentiated ll-day mouse kidney anlagen were transplanted onto quail chorioallantoic membrane and allowed to develop for 7-10 days. Upon examination, grafts were well-vascularized, and both the glomarular and the vessel endothelium expressed the quail nuclear marker. Similar results were obtained in quail/chick transplantation experiments. Hence, we suggest that the endothelium of the glomeruli is derived from outside vasculature rather than by conversion of cells in the nephrogenic masenchyme. interspecies transplantation kidney development vascularization
The cellular origin of fibronectin in the kidney was studied in three experimental models. Immuno... more The cellular origin of fibronectin in the kidney was studied in three experimental models. Immunohistochemical techniques that use cross-reacting or species-specific antibodies against mouse or chicken fibronectin were employed. In the first model studied, initially avascular mouse kidneys cultured on avian chorioallantoic membranes differentiate into epithelial kidney tubules and become vascularized by chorioallantoic vessels. Subsequently, hybrid glomeruli composed of mouse podocytes and avian endothelial-mesangial cells form. In immunohistochemical studies, cross-reacting antibodies to fibronectin stained vascular walls, tubular basement membranes, interstitium, and glomeruli of mouse kidney grafts. The species-specific antibodies reacting only with mouse fibronectin stained interstitial areas and tubular basement membranes, but showed no reaction with hybrid glomeruli and avian vascular walls. In contrast, species-specific antibodies against chicken fibronectin stained both the ...
Scandinavian Journal of Thoracic and Cardiovascular Surgery, 1986
During the years 1964-82 a total of 60 patients underwent surgery for aortic dissection. Forty of... more During the years 1964-82 a total of 60 patients underwent surgery for aortic dissection. Forty of them were males, with a mean age of 48.8 years (22 to 69) and 20 were females, with a mean age of 49.0 years (31 to 65). Forty-five patients were operated in an acute stage of aortic dissection and 15 patients in a chronic stage of this disease. The mortality rate of patients operated on for acute dissections was 51.1% and of patients with a chronic dissection 13.3%, the over-all hospital mortality rate being 41.7%. Cardiac and haemorrhagic complications were the commonest cause of death. Among the 35 operative survivors, there were seven late deaths (11.7%); 4 patients died of cardiovascular causes. The mean follow-up time was 6.1 years (2.7 to 13.4). Twenty-six long-term survivors were re-examined in the hospital.
Proceedings of the National Academy of Sciences, 1995
We analyzed the developmental regulation and role of the neurotrophins during metanephric kidney ... more We analyzed the developmental regulation and role of the neurotrophins during metanephric kidney morphogenesis. RNase protection assay revealed the presence of nerve growth factor, neurotrophin 3 (NT-3), and brainderived neurotrophic factor mRNAs and the regulation of their expression during embryonic development of rat metanephros. NT-3 induced differentiation (neurite outgrowth) and survival (inhibition of apoptosis) of the neuronal precursors in cultured nephrogenic mesenchymes and neuronal differentiation in cultured whole kidneys, whereas NT-4/5,
Two cases of breast tumors with a uniform solid carcinoid pattern and argyrophilic dense-core gra... more Two cases of breast tumors with a uniform solid carcinoid pattern and argyrophilic dense-core granules were analyzed by immunohistochemistry in order to compare their characteristics with known features of other carcinoid tumors and ordinary breast carcinomas. The tumors were positive for keratin-type intermediate filaments, neuron-specific enolase and alpha-chain of human chorion gonadotropin but negative for vimentin and S-100 protein. Laminin was found only in a rim between tumor cell islands and stroma but not among the cells. It is concluded that these tumors are histologically, ultrastructurally and immunohistochemically similar to other carcinoid tumors. The present results suggest that both breast carcinoids and carcinomas may have a common precursor in the mammary secretory unit.
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Papers by Hannu Sariola