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Vascular progenitor cells: origin and mechanisms of mobilization, differentiation, integration, and vasculogenesis.

The recent discovery of progenitor cells in peripheral blood that can differentiate into endothelial or vascular smooth muscle cells has led to the re-evaluation of many traditionally held beliefs about vascular biology. Most notably, concepts of vascular regeneration and repair, previously considered limited to the proliferation of existing differentiated cells within vascular tissue, have been expanded to include the potential for postnatal vasculogenesis. These cells have since been identified in the bone marrow, heart, skeletal muscle, and other peripheral tissues, including the vasculature itself. The significance of these cells lies not only in developing our understanding of normal vascular biology, but also in the insights they may provide into vascular diseases such as atherosclerosis. In addition, a potential role in therapeutics has already been explored in early clinical trials in humans. The mechanisms underlying the mobilization, target tissue integration, differentiation, and the observed therapeutic benefits of these cells are now being elucidated. It is these mechanisms, and the current understanding of the lineage of these cells, that constitutes the focus of this review.

Animals↗

Small cell carcinoma of the lung: macrophage-specific antigens suggest hemopoietic stem cell origin.

Four surface antigens previously recognized only in macrophages are present on human small cell lung carcinoma cells and tumors. Cancerous cells may arise from macrophage precursors in bone marrow, and these precursors migrate to lung to participate in the repair of damaged tissue produced by continuous heavy smoking. The characteristic presence of neuropeptides such as bombesin in small cell carcinoma, when considered along with these findings, presents new possibilities for the role of such peptides in nervous, endocrine, and immune system function.

Antigens, Neoplasm↗

Measurement of a follicle-stimulating hormone-responsive protein of Sertoli cell origin using an enzyme-linked immunoblot assay.

Many proteins secreted by Sertoli cell-enriched cultures are maximally stimulated by a combination of FSH and testosterone. Since very few are stimulated primarily by FSH, we thought it pertinent to identify such proteins. Sertoli cell-enriched cultures were prepared from testes of 20-day-old rats and grown in serum-free medium containing insulin, transferrin, and epidermal growth factor and in such medium supplemented with FSH, testosterone, or FSH plus testosterone. Media were fractionated using HPLC, and proteins were identified by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. A protein designated CMB-2, with an apparent mol wt of 22,000, was shown to increase in response to FSH. Antiserum was raised using denatured protein eluted from SDS-polyacrylamide gels as the antigen, and a specific immunoassay using a combination of SDS-polyacrylamide gel electrophoresis and Western blotting was developed. The production of CMB-2 by primary Sertoli cell-enriched cultures was found to increase in a dose-dependent manner in response to FSH (30-1000 ng/ml); secretion was not significantly affected by testosterone (2 X 10(-13) M). An investigation of the tissue distribution of CMB-2 showed that the puberty, CMB-2 is secreted into the rete testis and accumulates in the epididymis in high concentration. We conclude that CMB-2 will be a useful marker to study the action of FSH on the rat testis.

Androgen-Binding Protein↗

[Nasal lymphoma of natural killer cell origin].

We report a case of nasal lymphoma with characteristics of natural killer (NH) cells. A 44-year-old man was admitted to our hospital because of right nasal obstruction. Physical examination revealed a tumor in the right nasal cavity and swelling of the right cervical lymph nodes. Histopathological examination showed diffuse medium sized cell lymphoma. The neoplastic cells expressed CD2, NKH-1, HLA-DR and leukocyte common antigen, but lacked other T-cell, B-cell and myeloid markers. They were in germline configuration for immunoglobulin heavy chain and T-cell receptor genes by southern blot analysis. These findings suggest that they are derived from NK cell.

Adult↗

Ductular hepatocytes. Evidence for a bile ductular cell origin in furan-treated rats.

Cholangiolar-like structures composed of biliary epithelial cells and typically a single ductular hepatocytic cell in various stages of maturation appeared in association with an extensive bile ductular reaction within the atrophied right liver lobe of young adult Fischer 344 rats that had been subjected to a severely hepatotoxic treatment with furan. In contrast to normal cholangioles, these cholangiolar-like structures were completely surrounded by a basement membrane, which gave strong immunohistochemical staining reactions for both laminin and type IV collagen. All of the biliary epithelial cells and ductular hepatocytic cells exhibited a strongly positive immunohistochemical staining for gamma-glutamyl transpeptidase and for cytokeratin 8. Cytokeratin 19 was also strongly expressed in all of the biliary epithelial cells, but in just some of the ductular hepatocytic cells, whereas only the latter cells were immunohistochemically positive for albumin and contained peroxisomes in their cytoplasm. Cell junctions were formed between individual ductular hepatocytic cells and adjacent biliary epithelial cells of the same cholangiolar-like structures. In this novel model of severe hepatic injury, the range of cell and nuclear diameters characterizing the ductular hepatocytic cells, together with their phenotypic features, are consistent with a differentiation of rare bile ductular-like cells to transitional ductular cells to more mature ductular hepatocytes.

Animals↗

Neural crest cell origin for intrinsic ganglia of the developing chicken lung.

The development of intrinsic ganglia, comprised of neurons and glia cells that innervate airway smooth muscle, is a recognized component of the growing lung. However, the embryological origin of these neurons and glia is unclear. The lung buds develop as an outgrowth of the foregut, which contains migrating neural crest cells (NCC) that ultimately give rise to the enteric nervous system (ENS) along the entire length of the gut. It has therefore been proposed that the intrinsic ganglia of the lung arise from a subset of NCC that leave the gut and migrate into the lung buds during early development. We have tested this hypothesis using quail-chick interspecies grafting to selectively label the hindbrain-derived neural crest cell population that colonizes the gut. In conjunction with antibody labeling and in situ hybridization, we demonstrate that: (i) lung ganglia arise from vagal NCC that migrate from the foregut into the lung buds; (ii) like ENS precursors, these NCC express the transcription factor Sox10, and the receptors EDNRB and RET; (iii) the co-receptor for RET, GFRalpha1, is expressed in the lung mesenchyme and in ganglia; (iv) ganglia persist within the lung throughout development and contain cells immunopositive for the pan-neuronal markers ANNA-1 and PGP9.5, the inhibitory neurotransmitter NO, as shown by NADPH-diaphorase staining, and the glial marker GFAP.

Animals↗

Spontaneous follicular center cell lymphomas of B cell origin in cataract mice.

Spontaneous lymphomas from a strain of hereditary cataract (CAC-nct/+) mice were examined by light and electron microscopy and by immunohistochemical reaction for the mouse heavy and light immunoglobulin chains. Lymphomas occurred in 28 out of 45 male cataract mice and in 34 out of 52 females at 25 to 65 weeks of age. All of the lymphoma-bearing mice showed an enlargement of the spleen and mesenteric lymph nodes, and some mice also had hepatomegaly. Morphologically, all tumors were composed of a mixed population of small and large cells. Neoplastic cells had features of follicular center cell lymphomas, such as scant to moderate amounts of cytoplasm and cleaved and/or round nuclei with a large nuclear-to-cytoplasmic ratio. Large cells were often admixed with small cells, and had vesicular nuclei with prominent nucleoli juxtaposed to the nuclear membrane. Intracytoplasmic eosinophilic inclusions were observed in occasional cells, but Golgi apparatus was poorly developed and rough-surfaced endoplasmic reticulum was scant, unlike those in plasma cells. C-particles were seen in all lymphoma-bearing mice by electron microscopy. Intracisternal A-particles were detected in some mice. Immunohistochemically, neoplastic lymphoid cells were positive for the kappa light chain and the surface/cytoplasmic immunoglobulin M. These results indicate that lymphoid cell neoplasms found in hereditary cataract mice originate from follicular center B cells.

Animals↗

Expression of GCMB by intrathymic parathyroid hormone-secreting adenomas indicates their parathyroid cell origin.

GCMA and GCMB are related transcription factors that are critically important for embryological development of the placenta and parathyroid glands, respectively. Mice in which parathyroid glands have been surgically removed or fail to develop due to genetic loss of GCMB show continued production of PTH from a subset of thymic cells that express GCMA. In this study we examined whether human thymus produces PTH and/or GCMA and whether intrathymic PTH-secreting adenomas express GCMA or GCMB to determine the embryological origin of the secretory cells. By contrast to mouse thymus, analysis of 22 samples of human thymus tissue by RT-PCR and/or immunohistochemistry failed to demonstrate the expression of either PTH or GCMA. RT-PCR analysis of 16 intrathymic adenomas from patients with surgically cured primary hyperparathyroidism showed that these tumors expressed PTH and GCMB and not GCMA. We conclude that the normal human thymus does not express GCMA or PTH, and therefore, in contrast to the mouse, the human thymus is not a source of PTH production. Finally, intrathymic PTH-secreting adenomas express the parathyroid-specific GCMB gene, which suggests that these tumors were derived from parathyroid cells that migrated errantly during embryogenesis.

Adenoma↗

p53 gene mutations are rare in patients but common in patient-originating cell lines in multiple myeloma.

We have shown previously that detectable serum concentration of p53 protein is associated with poor prognosis in multiple myeloma (MM). In this study, we studied p53 gene mutations in 29 bone marrow samples of MM patients using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and direct sequencing. No p53 mutations were found in these patients although 41% of the patients had an elevated serum p53 protein concentration. This result indicates that the detectable serum level of p53 protein is not associated with p53 mutations. In addition, we have also analysed three MM cell lines established from bone marrow samples. All the cell lines contained p53 mutations in exon 5. However, bone marrow samples of the patients associated with the cell lines did not have these mutations at the time of diagnosis, nor did the original samples which were used to establish the cell lines. This indicates that p53 mutations can arise during the cell passages.

Adult↗

Interdigitating cell sarcoma (ICS). Evidence of interdigitating cell origin, immunocytochemical studies with monoclonal anti-ICS antibodies.

Three independent mouse monoclonal antibodies (mAbs) ID1 (IgG3), ID2 and ID3 (IgM) were raised against whole cells of a surgically resected human interdigitating cell sarcoma (ICS). In immunoperoxidase staining, these mAbs strongly stained the cytoplasm of ICS neoplastic cells as well as interdigitating cells in normal lymphoid tissues. These mAbs also detected monocyte/macrophages and dendritic cells, although their staining was highly variable depending on tissue distribution of the cells. Additional immuno-histological and enzyme histochemical study revealed that the neoplastic cells of ICS had cytoplasmic acid phosphatase and membranous alkaline phosphatase activity, and also possessed S100 beta protein, Ki-1 antigen. DAKO-macrophage antigen, and weak vimentin activity. Neither rearrangement of immunoglobulin heavy chain gene nor of T-cell receptor genes was detected in the DNA of ICS by Southern hybridization. These observations provide further confirmation of our previous finding (Nakamura et al. 1988, 1989) that the origin of ICS is interdigitating rather than lymphoid cell, and indicate that our mAbs could be useful as a cellular differentiation marker of interdigitating cells and for diagnosis of ICS.

Animals↗

Evidence for pluripotent stem cell origin of idiopathic myelofibrosis: clonal analysis of a case characterized by a N-ras gene mutation.

Three cases of idiopathic myelofibrosis were screened for the presence of mutations at codon 12, 13, or 61 of the ras gene family by a rapid method based on polymerase chain reaction and hybridization to mutation-specific oligonucleotides. PB cells of one patient showed a point mutation at codon 12 of the N-ras oncogene. This molecular genetic hallmark was used to investigate the clonal relationship of different cell lineages by cell separation analysis. Presence of the N-ras 12 mutation in granulocytes, monocytes, B cells, and T lymphocytes, as well as erythroblasts, indicates that idiopathic myelofibrosis originates from a pluripotent stem cell, at least in this patient.

Clone Cells↗

Phospholipid composition and ultrastructure of A549 cells and other cultured pulmonary epithelial cells of presumed type II cell origin.

In order to assess the usefulness of A549, L-2, and AK-D cell lines as model systems for alveolar type II cells, we compared their phospholipid composition to that of fibroblasts grown under similar conditions. The percentage of disaturated phosphatidylcholine and phosphatidylglycerol, key phospholipids of purified surface-active material, was the same in epithelial cells and fibroblasts. When A549 cells were maintained in serum-free media for two days, ultrastructural examination showed an increase in cytoplasmic lamellar inclusions but there was no change in the percentage of disaturated phosphatidylcholine or phosphatidylglycerol. Because the lipid content of these cultured cells was very different from that of freshly isolated rat type II cells, we conclude that their suitability as model cell systems for type II cells is questionable.

Adenocarcinoma, Bronchiolo-Alveolar↗