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PubMed2004

[Cellular aspects of bone regeneration: role of bone marrow periostium].

Bone regeneration is only possible if stem cells give rise to progenitors of osteoblasts, chondroblasts or chondroidocytes. Stem cells and osteogenic progenitors were evidenced in bone marrow while only progenitors can be found in periosteum. Bone marrow stem cells did show an amazing plasticity and some cells of the bone surrounding tissues such as perivascular cells, adipocytes, muscle cells or even circulating cells are able to transdifferentiate in osteoblasts when submitted to an osteogenic environment. We have shown that the destruction of both bone marrow and periost impairs the bone healing. It indicates that the periost and bone marrow destruction removes the predetermined osteogenic cells and the informative factors able to induce the transdifferenciation of the cells contained in the peri-osseous tissues.

Bone Marrow↗
PubMed2003

The role of human achaete-scute homolog-1 in medullary thyroid cancer cells.

BACKGROUND: Human achaete-scute homolog-1 (hASH1) is a transcription factor that is expressed highly in neuroendocrine tumors such as medullary thyroid cancer (MTC). Thyroid C-cells do not develop in hASH1 knockout mice, which suggests that hASH1 is essential for normal C-cell development. METHODS: To determine the effect of raf-1 induction on hASH1 and hormone production, we used an estrogen inducible raf-1 construct in MTC cell line (TT) cells (TT-raf cells). TT or TT-raf cells were treated with control or 1 microM estradiol. After 48 hours, the cells were analyzed for levels of hASH1 and chromogranin A by Western blotting and for calcitonin production by enzyme-linked immunosorbent assay. RESULTS: Activation of raf-1 in the TT-raf cells resulted in high levels of phosphorylated MEK and ERK1/2, a morphologic transdifferentiation, and a decrease in chromogranin A and calcitonin levels that are associated with a reduction in hASH1 production. Furthermore, using MEK inhibitors, we demonstrated that these raf-1-mediated changes are dependent on MEK but not ERK1/2 activation. CONCLUSION: hASH1 down-regulation by raf-1 in MTC cells is associated with a significant decrease in hormone production. Thus, hASH1 appears to be important in the endocrine phenotype of MTC tumors and may serve as a molecular target for the treatment of patients with MTC.

Basic Helix-Loop-Helix Proteins↗
PubMed2006

7. Transplantation of undifferentiated, bone marrow-derived stem cells.

Stem cell research has known an enormous development, and cellular transplantation holds great promise for regenerative medicine. However, some aspects, such as the mechanisms underlying stem cell plasticity (cell fusion vs true transdifferentiation) and the functional improvement after stem cell transplantation, are highly debated. Furthermore, the great variability in methodology used by several groups, sometimes leads to confusing, contradicting results. In this chapter, we review a number of studies in this area with an eye on possible technical and other difficulties in interpretation of the obtained results.

Animals↗
PubMed1986

Nematocyte differentiation in hydra.

Nematocyte differentiation from interstitial stem cells in hydra occurs in a highly position-dependent manner along the body axis. The results of the studies summarized here have shown that the morphogenetic factors involved in head formation are probably not responsible for this. Whether the morphogenetic factors involved in foot formation are responsible has not been determined. A new factor, presumably unrelated to any of the known morphogens, has been identified which specifically inhibits the developing nematoblasts to differentiate into stenoteles. This factor is present in a gradient along the body column, and appears to be responsible, at least in part, for producing position-dependent nematocyte differentiation. Nematoblasts which normally differentiate into one nematocyte type can be altered to differentiate into another by means of regeneration or treatment with stenotele inhibitor. This alteration occurs near the S/G2 boundary in the terminal cell cycle in the nematocyte differentiation pathway. It appears that either the nematoblasts are not committed to any specific nematocyte pathway until this critical time, or the nematoblasts committed to differentiate into a specific type can transdifferentiate into another type at this step.

Animals↗
PubMed1999

The pecten oculi of the chicken: a model system for vascular differentiation and barrier maturation.

The pecten oculi is a convolute of blood vessels in the vitreous body of the avian eye. This structure is well known for more than a century, but its functions are still a matter of controversies. One of these functions must be the formation of a blood-retina barrier because there is no diffusion barrier for blood-borne compounds available between the pecten and the retina. Surprisingly, the blood-retina barrier characteristics of this organ have not been studied so far, although the pecten oculi may constitute a fascinating model of vascular differentiation and barrier maturation: Pectinate endothelial cells grow by angiogenesis from the ophthalmotemporal artery into the pecten primordium and consecutively gain barrier properties. The pectinate pigmented cells arise during development from retinal pigment epithelial cells and subsequently lose barrier properties. These inverse transdifferentiation processes may be triggered by the peculiar microenvironment in the vitreous body. In addition, the question is discussed whether the avascularity of the avian retina may be due to the specific metabolic activity of the pecten.

Animals↗
PubMed2003

Molecular biology of hematopoietic stem cells.

Human CD34+ hematopoietic stem and progenitor cells are capable of maintaining a life-long supply of the entire spectrum of blood cells dependent on systemic needs. Recent studies suggest that hematopoietic stem cells are, beyond their hematopoietic potential, able to differentiate into nonhematopoietic cell types, which could open novel avenues in the field of cellular therapy. Here, we concentrate on the molecular biology underlying basic features of hematopoietic stem cells. Immunofluorescence analyses, culture assays, and transplantation models permit an extensive immunological as well as functional characterization of human hematopoietic stem and progenitor cells. New methods such as cDNA array technology have demonstrated that distinct gene expression patterns of transcription factors and cell cycle genes molecularly control self-renewal, differentiation, and proliferation. Furthermore, several adhesion molecules have been shown to play an important role in the regulation of hematopoiesis and stem cell trafficking. Progress has also been made in elucidating molecular mechanisms of stem cell aging that limit replicative potential. Finally, more recent data provide the first molecular basis for a better understanding of transdifferentiation and developmental plasticity of hematopoietic stem cells. These findings could be helpful for non-hematopoietic cell therapeutic approaches.

Antigens, CD34↗
PubMed2003

Differentiation of human bone marrow-derived cells into buccal epithelial cells in vivo: a molecular analytical study.

BACKGROUND: Adult bone marrow-derived (BMD) cells could be used to repair damaged organs and tissues, but the intrinsic plasticity of these cells has been questioned by results of in-vitro studies suggesting that such cells might fuse with other cells giving the appearance of differentiation. We aimed to determine whether fusion events are important in vivo. METHODS: To test whether BMD cells can colonise an epithelial tissue and differentiate there without fusion, we did in-situ hybridisation with Y and X chromosome probes labelled with 35-sulphur or digoxigenin, or labelled fluorescently. We did immunohistochemistry with anticytokeratin 13 along with fluorescence in-situ hybridisation to identify Y-chromosome positive buccal epithelial cells in cheek scrapings obtained from five females who had received either a bone-marrow transplant or an allogeneic mobilised peripheral-blood progenitor-cell transplant (enriched in CD34+ cells) from male donors. FINDINGS: When examined 4-6 years after male-to-female marrow-cell transplantation, all female recipients had Y-chromosome-positive buccal cells (0.8-12.7%). In more than 9700 cells studied, we detected only one XXXY-positive cell (0.01%) and one XXY cell (0.01%), both of which could have arisen when an XY cell fused with an XX cell. INTERPRETATION: Male BMD cells migrate into the cheek and differentiate into epithelial cells, an occurrence that does not depend on fusion of BMD cells to recipient cells. This finding might be an example of transdifferentiation of haemopoietic or stromal progenitor cells. Plasticity of BMD cells could be useful in regenerative medicine.

Adult↗
PubMedDate not supplied

Stem-cell therapy for diabetes mellitus.

CONTEXT: Curative therapy for diabetes mellitus mainly implies replacement of functional insulin-producing pancreatic beta cells, with pancreas or islet-cell transplants. However, shortage of donor organs spurs research into alternative means of generating beta cells from islet expansion, encapsulated islet xenografts, human islet cell-lines, and stem cells. Stem-cell therapy here implies the replacement of diseased or lost cells from progeny of pluripotent or multipotent cells. Both embryonic stem cells (derived from the inner cell mass of a blastocyst) and adult stem cells (found in the postnatal organism) have been used to generate surrogate beta cells or otherwise restore beta-cell functioning. STARTING POINT: Recently, Andreas Lechner and colleagues failed to see transdifferentiation into pancreatic beta cells after transplantation of bone-marrow cells into mice (Diabetes 2004; 53: 616-23). Last year, Jayaraj Rajagopal and colleagues failed to derive beta cells from embryonic stem cells (Science 2003; 299: 363). However, others have seen such effects. WHERE NEXT? As in every emerging field in biology, early reports seem confusing and conflicting. Embryonic and adult stem cells are potential sources for beta-cell replacement and merit further scientific investigation. Discrepancies between different results need to be reconciled. Fundamental processes in determining the differentiation pathways of stem cells remain to be elucidated, so that rigorous and reliable differentiation protocols can be established. Encouraging studies in rodent models may ultimately set the stage for large-animal studies and translational investigation.

Animals↗
PubMed1984

Possible mechanisms for the loss of goblet cells in mucin-deficient disorders.

By studying the pathological changes in human conjunctival flaps and the conjunctival transdifferentiation in rabbits, we have identified and correlated two pathological processes with the loss of goblet cells: (1) loss of vascularization, and (2) intense inflammation. Loss of vascularization may be correlated with the loss of goblet cells in the chronic cicatricial stage of various mucin-deficient disorders, whereas inflammation may be responsible for their absence in the acute inflammatory stage. The exact interrelationship between these two processes remains unknown. The loss of goblet cells appears to be an early sign of a spectrum of squamous metaplasia, an abnormality of epithelial differentiation. We therefore speculate that loss of vascularization and intense inflammation may have an important effect on epithelial differentiation.

Adult↗
PubMed2003

Clonal expansion and not cell interconversion is the basis for the neuroblast and nonneuronal types of the SK-N-SH neuroblastoma cell line.

The ability of neuroblastoma (NB) cells to interconvert bidirectionally, in vitro, from a neuroblast (N) to a nonneuronal (S) form is a well-studied biologic phenomenon of great clinical importance. Differences in the morphologic/ biochemical characteristics and gene expression patterns of the two cell populations have been investigated extensively in an effort to unravel the transdifferentiation process. Subcloning of the SK-N-SH NB cell line has led to two morphologically distinct cell types: SH-SY5Y (N-type) and SH-EP (S-type). Karyotypic analysis combined with G-banding and SKY showed a difference between these two cell types in the copy number of the 2p15 approximately pter segment, including the MYC-N gene. FISH analysis showed an extra copy of MYC-N present in all three lines: in SK-N-SH and SH-SY5Y the majority of cells had three copies of MYC-N, whereas in SH-EP the majority had two copies and only a small cell population with three copies was present. We suggest that the simultaneous coexistence of both cell types and the subsequent clonal expansion of one over the other is a possible explanation for the phenomenon observed and not the accepted interconversion model. According to the clonal expansion model, both N and S cells are simultaneously present in both cell lines. Under certain conditions, the less-aggressive S cells can dominate over the highly aggressive N cells, which eventually lead to the formation of the SH-EP and vice-versa.

Cell Differentiation↗
PubMed2003

A glimmer of hope for diabetics?

Diabetes affects 150 million people worldwide and results from abnormal function of pancreatic islets. The scarcity of human tissue donors has focused interest in developing renewable sources of insulin-producing cells appropriate for engraftment. Advances in stem cell technology and transdifferentiation techniques have provided powerful tools to study pancreatic development, function and disease. Recent results from these two approaches could have significant implications for future therapies of diabetes.

Cell Differentiation↗
PubMed2001

5'-Methylthioadenosine administration prevents lipid peroxidation and fibrogenesis induced in rat liver by carbon-tetrachloride intoxication.

BACKGROUND: 5'-Methylthioadenosine (MTA), a product of S-adenosylmethionine (SAM) catabolism, could undergo oxidation by mono-oxygenases and auto-oxidation. MTA and SAM effects on oxidative liver injury were evaluated in CCl4-treated rats. METHODS: Male Wistar rats were killed 1-48 h after poisoning with a single intraperitoneal CCl4 dose (0.15 ml/100 g) or with the same dose twice a week for 14 weeks. Daily doses of MTA or SAM (384 micromol/kg), started 1 week before acute CCl4 administration or with chronic treatment, were continued up to the time of sacrifice. RESULTS: Acute and chronic CCl4 intoxication decreased MTA and, to a lesser extent, SAM and reduced glutathione (GSH) liver levels. MTA administration increased liver MTA without affecting SAM and GSH. SAM treatment caused complete/partial recovery of these compounds. MTA and, to a lesser extent, SAM prevented an increase in liver phospholipid hydroperoxides in acutely and chronically intoxicated rats and in prolyl hydroxylase activity and trichrome-positive areas in chronically treated rats. MTA prevented upregulation of Tgf-beta1, Collagen-alpha1 (I) and Tgf-alpha genes in liver of chronically intoxicated rats, and TGF-beta1-induced transdifferentiation to myofibroblasts and growth stimulation by platelet-derived growth factor-b of stellate cells in vitro. CONCLUSIONS: MTA and SAM protect against oxidative liver injury through partially different mechanisms.

Acute Disease↗
PubMed2000

Alkaline phosphatase expression during monocyte differentiation. Overlapping markers as a link between monocytic cells, dendritic cells, osteoclasts and osteoblasts.

Human monocytes (Mo) in culture can be differentiated into macrophages (M phi), dendritic cells (DC) and osteoclasts. In addition, we have established a Mo-derived in vitro granuloma model which here was compared with ex-vivo isolated foreign body granuloma cells. In these models overlapping phenotypes developed between monocyte-derived dendritic cells (MoDC), osteoclasts, M phi, and osteoblasts. In Mo cultures granulomas were induced by immobilized particulate material. AP activity (osteoblast marker) was found to be co-expressed with cytoplasmic tartrate resistant acid phosphatase (TRAP) as a marker of osteoclasts. While proliferating, the number of AP+ cells decreased, being replaced by cells co-expressing the osteoclast markers vitronectin receptor (VNR) and TRAP. Coexpression of the Mo/M phi marker CD68 with AP or VNR confirmed the monocytic origin of the cells. When Mo were treated with interleukin-4 (IL-4), the number of AP+ cells markedly increased and remained stably expressed over 12 days. In explants from ex vivo granulomas obtained from endoprosthetic revisions the major cell type was the AP+ cell co-expressing CD68. The bone-specific alkaline phosphatase (BAP) as a marker of osteoblasts was detected by FACS analysis in the ex vivo granuloma cells. By RT-PCR the mRNA for osteocalcin, which is a highly specific marker for osteoblasts, was detected. From our results we conclude an ontogenetic relationship between macrophages, DC and osteoclasts. Furthermore, the data suggest a transdifferentiation between Mo and osteoblasts.

Alkaline Phosphatase↗
PubMed1998

Phenotypical changes of a human pancreatic adenocarcinoma cell line after selection on laminin-1/nidogen (LM/Ng) substratum.

A cell line (PaTu 8902LM) exhibiting an altered phenotypic appearance was selected from a highly dedifferentiated established human pancreatic tumour cell line (PaTu 8902) by repetitive exposure to laminin-1/nidogen substratum and subsequent selection for adherent cells. Polymerase chain reaction analysis for repetitive DNA indicated that both cell lines are genetically very closely related. The original PaTu 8902 line consisted of flat cells growing in monolayers. In contrast, the obtained PaTu 8902LM cells exhibited a spherical morphology and tended to form clusters. Immunofluorescence analysis using antibodies against apical and basolateral marker enzymes indicated that the PaTu 8902LM cells were polarized, arranging their apical surfaces around central lumenal structures when growing in clusters. In addition, the selected PaTu 8902LM cell line exhibited altered levels of a number of differentiation marker enzymes like 5'-nucleotidase, transglutaminase and plasminogen activators. The different morphological characteristics of both cell lines were maintained even after injection into nude mice. In xenografts, PaTu 8902LM cells were grouped around lumenal, duct-like structures, whereas the original PaTu 8902 cell line formed solid tumours composed of undifferentiated cells. Evidence is presented that the PaTu 8902LM cells are not merely selected from preexisting cells, but that the exposure of PaTu 8902 cells to laminin-1/nidogen had induced a stable transdifferentiation towards the phenotype of the epithelial cells lining the pancreatic secretory ducts. Thus the PaTu 8902LM cells resemble more closely those cells from which tumours of the pancreas originate in vivo and therefore might be a useful cell system in future analyses of the biology of pancreatic tumours which are of increasing incidence and clinical importance.

Adenocarcinoma↗
PubMed2005

[Which stem cells for adult liver?].

While hepatocytes can be considered conceptually as unipotent stem cells, the presence of true stem or progenitor cells within adult livers has been largely debated. It is now accepted that the atypical ductular reaction observed in livers with sub-massive hepatitis represents the proliferation of hepatic progenitor cells similar to rat oval cells and able to differentiate towards the biliary and the hepatocytic lineage through intermediate progeny. In the normal liver, the identification of progenitor cells with a panel of markers including c-kit, CD34, Ov6, CK7, CK19, chromogranine A, CD56 remains difficult because these cells are very few and most of the markers are not specific. These progenitor cells could be located either within the canals of Hering or in periductular situation or both. Mechanisms leading to the activation and the proliferation of hepatic progenitor cells are still largely unknown: they involve growth factors as the stem cell factor, ligand of c-kit, cytokines, chemokines as SDF1 a and vagal or sympathetic innervatioñ. Other potential stem cells for liver could be hematopoietic stem cells from bone marrow. First publications have showed that hematopoietic stem cells were able to differentiate into hepatocytes and cholangiocytes and to yield high level engraftment of injured livers. However it appears now that this phenomenon is minimal or even absent in physiological and usual pathological conditions. It does occur in extreme experimental conditions either by true transdifferentiation or cell fusion. The shared property of stem cells and tumor cells to proliferate endlessly, rises the question of the potential role of progenitor cells in liver carcinogenesis. In a number of animal models of hepatocarcinogenesis, tumors originate from oval cells. The identification of progenitor cells close to murine oval cells in the human liver raises the hypothesis of a potential role of these cells in the development of human liver tumors. Liver progenitor cells have been identified morphologically and phenotypically in dysplastic foci of cirrhotic livers and hepatocellular adenomas. More generally speaking, typical hepatocellular carcinomas and cholangiocarcinomas are at the two ends of a spectrum which includes transitional-type tumors intermediate between hepatocellular carcinoma and cholangiocarcinoma and combined hepato-cellular cholangiocarcinoma; these intermediate and combined types can be more easily explained as deriving from progenitor cells. Despite the difficulties, the doubts and the potential dangers, new experimental modalities to obtain efficient repopulation of the liver from bone marrow stem cells are currently under study: exogenous administration of cytokines and chemokines involved in cell homing and differentiation or development of selective pressure strategies. Other cell types as intra-hepatic progenitor cells, bone marrow multipotent adult progenitor cells (MAPCs) or fetal hepatocytes could be alternative sources for liver cell therapy. Thus, progressing knowledge about stem cells in adult liver would allow to better understand mechanisms of hepatic homeostasia and regeneration and would open the way to cell-based therapy for liver diseases.

Adult↗
PubMed2002

Cells with hemopoietic potential residing in muscle are itinerant bone marrow-derived cells.

OBJECTIVE: The nature of cells residing in muscle giving rise to hemopoietic colonies in vitro or hemopoietic reconstitution in vivo has been unclear. The goal of the present study was to characterize these cells and uncover their potential site of origin. MATERIALS AND METHODS: Cells prepared from muscle were characterized for surface antigens (CD45, CD34, c-kit, Sca-1, CD31, VCAM-1), for their in vitro clonogenic capacity and in vivo repopulation potential either as unpurified cells or sorted subsets (CD45(+), CD45(-)). The presence of bone marrow (BM)-derived cells in muscle of mice reconstituted with marked BM cells before and after cytokine-induced mobilization was also examined. RESULTS: Our data show: 1) The yield of CD45(+) cells is higher in muscle of neonates and young animals. Their composite phenotype does not favor contamination by blood. 2) The capacity of fresh muscle cell explants to give rise to colonies in vitro and hemopoietic reconstitution in vivo is associated with CD45(+) cells. 3) Irradiated recipients reconstituted with marked BM cells harbor marked BM-derived cells (CD45(+) or CD45(-)) in their muscle several months after transplant. 4) Cytokine-induced mobilization of transplanted animals modestly increases the yield of BM-derived cells recovered from muscle, unlike the yields from spleen, liver, or peripheral blood (PB). CONCLUSIONS: Our data suggest a reinterpretation of previously published conclusions: hemopoietic colonies derived from fresh muscle explants do not originate from transdifferentiated muscle cells, but from BM-derived cells residing in muscle; the hemopoietic reconstituting potential of muscle cells is likewise attributed to these cells.

Animals↗
PubMed2002

Primate skeletal muscle contains cells capable of sustaining in vitro hematopoiesis.

OBJECTIVE: Several investigators recently reported that adult murine skeletal muscle cells possess a remarkable capacity to differentiate into hematopoietic cells. We further examined this biologic process by studying the phenotype and in vitro functional behavior of primate skeletal muscle cells. MATERIALS AND METHODS: Muscles from human abortuses as well as fetal and adult baboons were digested enzymatically and mononuclear cell fractions were isolated. Muscle tissue-derived mononuclear cells (mu-TDMNC) were phenotypically characterized. Both short-term and long-term hematopoietic progenitors were assayed from mu-TDMNC using standard techniques. Gene expression patterns characteristic of hematopoietic and endothelial cells were examined in primary and cultured muscle cells. RESULTS: Primate muscle cells were shown to express the CD34 antigen. Such CD34(+) cells were shown to be CD45(-) and desmin(+), indicating they were not of hematopoietic origin. Fetal but not adult muscle cells contained assayable hematopoietic progenitors. In addition, muscles contained an additional class of progenitors that formed colonies composed of blast cells after prolonged incubation (3-4 weeks). A two-step culture system was established that permitted muscle cells to continue to proliferate when exposed to a hematopoietic environment for 8 months. During this prolonged period of time, the generation of CD34(+), CD56(+), CD11b(+), and CD31(+) as well as von Willebrand factor (vWF)(+) cells were observed. CONCLUSIONS: Our studies indicate that although primate muscle cells contain a significant number of CD34(+) cells, they are likely not of hematopoietic origin. Important ontogenic differences in the hematopoietic potential of primate muscle cells were documented. When exposed to appropriate microenvironmental stimuli, mu-TDMNC displayed an extensive proliferative capacity and contained primitive progenitors with the capacity to generate cells in vitro with phenotypic and genetic properties of hematopoietic and endothelial cells for sustained periods of time. Whether this observation can be accounted for by true transdifferentiation of muscle cells or proliferation of reservoirs of hematopoietic and endothelial progenitor cells residing within skeletal muscle remains unresolved.

Age Factors↗
PubMed1989

Ultrastructural and immunocytochemical characterization of the cellular phenotype in primary adenoid liver tumours of the rat.

The cellular phenotype of 34 primary adenoid liver tumours induced in rats with N-nitrosomorpholine was studied by immunocytochemical and electron microscopical methods in order to elucidate the histo- and cytogenesis of these tumours. Three types of ducts were distinguished in the adenoid liver tumours at the ultrastructural level being characterized as of hepatocellular, transitional and cholangiocellular phenotype. The transitional cells took an intermediate position between the hepatocellular and the cholangiocellular phenotype. Frequent features of the hepatocyte-like differentiation were large round nuclei with a dispersed chromatin, glycogen-associated ER complexes, peroxisomes and the formation of bile canaliculi. Evidence for the relationship to bile ductular cells was provided by the regular association with a basement membrane, the (inconstant) positive immunohistochemical reaction for cytokeratin polypeptide KA-4, a poorly developed ER and small mitochondria. An additional finding in the ducts with a transitional cellular phenotype was the selective accumulation of mast cells integrated into the epithelium. Intimate associations between cells of the hepatocellular, transitional and cholangiocellular phenotype were observed at the light and electron microscopic level. The results suggest that a transdifferentiation (metaplasia) from cells with a hepatocellular to those with a transitional or cholangiocellular phenotype takes place in many liver tumours.

Adenoma↗