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PubMed2004

[Chemokine directed homing of transplanted adult stem cells in wound healing and tissue regeneration].

A major challenge in stem cell biology is to study the underlying mechanisms of tissue specific homing and differentiation. Recent results suggest that bone marrow derived stem cells can give rise to multiple cell types. Because chemokines and chemokine receptors are associated with development, differentiation and homing of immune cells, we undertook efforts to study the chemokine receptor expression profile of human adult stem cells to identify their potential role in tissue specific homing prior to transdifferentiation. Using human bone marrow-derived stem cell lines, we could demonstrate functional chemokine receptor expression of various chemokine receptors. The expression of CXCR5 and CCR7, associated with secondary lymphoid organ homing as well as CXCR4 and CCR10, involved in organ specific homing and CXCR3, CCR5 and CCR1, which are involved in inflammation events, suggested a role of chemokine receptors in tissue specific homing of stem cells. To proof the specific homing of stem cells in vivo, we used murine stem cell lines, stably introduced green fluorescent protein under control of CMV promotor into the cells and injected them intravenously into mice. We demonstrate the homing of these stem cells to lymphnode and thymus as well as mucosal tissue, while stem cells home exclusively to a site of lesion during wound healing and tissue regeneration. Our data suggest that chemokine biology may play a pivotal role in the homing of stem cells to specific tissues and niches prior to (trans)differentiation, while the homing changes during tissue damage and other adequate lesions.

Adult↗
PubMed2006

[Umbilical cord blood as a source of stem cells].

Umbilical cord blood (UCB) is a source of the rare but precious primitive hematopoietic stem cells (HSC) and progenitor cells that can reconstitute the hematopoietic system in patients with malignant and nonmalignant disorders treated with myeloablative therapy. UCB cells possess an enhanced capacity for progenitor cell proliferation and self-renewal in vitro. UCB is usually discarded, and it exists in almost limitless supply. The blood remaining in the delivered placenta is safely and easily collected and stored. The predominant collection procedure currently practiced involves a relatively simple venipuncture, followed by gravity drainage into a standard sterile anti-coagulant-filled blood bag, using a closed system, similar to the one utilized on whole blood collection. After aliquots have been removed for routine testing, the units are cryopreserved and stored in liquid nitrogen. UCB banks are being established throughout the world and UCB units are collected for allogeneic unrelated and related HSC transplantation. In unrelated cord blood banks donated UCB units are collected and stored for allogeneic use in patients who do not have an identified HLA matched relative. UCB banks report available units to national and international donor registries. The second model of UCB banking is referred to as family banking, where UCB is stored for the benefit of the donor or their family members. After more than one decade of clinical experience, it is currently accepted that UCB transplants, related and unrelated, are equivalent to or might compare favorably with bone marrow (BM) transplants, especially in children. Initial studies of long-term survival in children with both malignant and non-malignant hematologic disorders, who were transplanted with UCB from a sibling donor, demonstrated comparable or superior survival to children who received BM transplantation. One factor that limits the use of UCB transplantation in adult patients is the relatively limited number of HSC that may be harvested from umbilical cord, resulting in a slower time to engraftment and higher transplant related mortality, mainly due to the long aplasia period after transplantation and susceptibility to viral and fungal infections. Despite prolonged periods of aplasia, the apparent reduction in the incidence and severity of graft versus host disease (GVHD) may in turn underline comparable rates of survival in some series comparing UCB to adult-donor sources. The "naive" nature of UCB lymphocytes may explain the lower incidence and severity of GVHD encountered in UCB transplantation compared to the allogeneic BM transplant setting. UCB transplantation does not seem to be associated with increased rates of disease relapse. The available data suggest that nucleated cell dose in UK unit should be the primary criterion for donor selection. In 1991, the UCB transplantation program was established at the Zagreb University Hospital Center for related transplants, and until now 4 UCB transplantations have been performed successfully. In order to speed up the engraftment rate, several strategies such as multiple UCB transplants and ex vivo expansion of HSC have been assayed. The current strategies are focused on the development of much more efficient technologies for ex vivo production of progenitor cells, but whether expansion will speed engraftment and improve outcome after UCB remains to be determined. UCB is known to contain extremely immature stem cells. Consequently, such pluripotent or, perhaps, multipotent stem cells have been proposed as elements suitable for cellular therapy and regenerative medicine. Up to date there are no conclusive data regarding these possibilities but preliminary in vitro and animal studies in the field of tissue regeneration suggest some degree of plasticity and/or transdifferentiation. UCB cells are showing their unique qualities and potential, and consequently UCB banks might dramatically increase the scope of their clinical application.

Blood Banks↗
PubMedDate not supplied

Adenovirus-based transient expression systems for peritoneal membrane research.

BACKGROUND: Peritoneal membrane research has provided important insights into the physiology and pathophysiology of this tissue that is of vital importance for peritoneal dialysis patients. Among the various tools and methodologies used to study the peritoneum, we have extensively used adenovirus-mediated gene transfer. METHODS: A literature review was carried out. Information from reviewed papers was combined with the authors' experience and results. RESULTS: We have used first-generation adenoviruses that are simple to construct and can infect a wide range of dividing and nondividing cell types. These vectors are restricted, however, in that they provide only a short duration of transgene expression and may elicit an inflammatory response. Modifications to this technology with helper-dependent adenovirus may circumvent these problems but with increased complexity of construction. Adenovirus-mediated gene transfer has been used to evaluate the effect of several cytokines and growth factors on peritoneal membrane physiology. We have used intraperitoneal delivery of transforming growth factor-beta to generate an experimental model system of resolving peritoneal fibrosis and epithelial mesenchymal transdifferentiation. We have studied the effects of the inflammatory cytokines interleukin-1beta and tumor necrosis factor alpha on the peritoneum, and have shown that antiangiogenic factors such as sFLT-1 and angiostatin can reduce the damaging effects of exposure to peritoneal dialysis solutions in an animal model. CONCLUSIONS: The use of recombinant adenoviruses to genetically modify cells and tissues is now a common laboratory research tool. This technique has provided important advances in our understanding of the peritoneal membrane.

Adenoviridae↗
PubMedDate not supplied

[Mesenchymal stem cells. A review.].

The bone marrow contains various types of stem cells. Among them are hematopoietic stem cells, which are the precursors of all blood cells, and mesenchymal stem cells. Mesenchymal stem cells have recently received a lot of attention in biological research because of their capability to self renewal, to expand and transdifferentiate into many different cell types; bone cells, adipocytes, chondrocytes, tendocytes, neural cells and stromal cells of the bone marrow. Mesenchymal stem cells can be cultured in vitro although their differentiation potential is not yet fully understood. Several experiments have been conducted in animal models where mesenchymal stem cells have been transplanted in order to enhance hematopoiesis or to facilitate the repair of mesenchymal tissue. Similar experiments are being conducted in humans. Mesenchymal stem cells are believed to be able to enhance hematopoietic stem cells transplantation by rebuilding the bone marrow microenvironment which is damaged after radiation- and/or chemotherapy. Mesenchymal stem cells are promising as vehicles for gene transfer and therapy. It may prove possible to tranduce them with a gene coding for a defective protein i.e. collagen I in osteogenesis imperfecta. The cells could then be expanded ex vivo and transplanted to the patients where they home to the bone marrow, differentiate and produce the intact protein. Future medicine will probably involve mesenchymal stem cells in various treatment settings.

English Abstract↗
PubMed2006

Progress of cellular dedifferentiation research.

Differentiation, the stepwise specialization of cells, and transdifferentiation, the apparent switching of one cell type into another, capture much of the stem cell spotlight. But dedifferentiation, the developmental reversal of a cell before it reinvents itself, is an important process too. In multicellular organisms, cellular dedifferentiation is the major process underlying totipotency, regeneration and formation of new stem cell lineages. In humans, dedifferentiation is often associated with carcinogenesis. The study of cellular dedifferentiation in animals, particularly early events related to cell fate-switch and determination, is limited by the lack of a suitable, convenient experimental system. The classic example of dedifferentiation is limb and tail regeneration in urodele amphibians, such as salamanders. Recently, several investigators have shown that certain mammalian cell types can be induced to dedifferentiate to progenitor cells when stimulated with the appropriate signals or materials. These discoveries open the possibility that researchers might enhance the endogenous regenerative capacity of mammals by inducing cellular dedifferentiation in vivo.

Animals↗
PubMed2006

[Cell therapy for Duchenne muscular dystrophy].

Duchenne muscular dystrophy (DMD) is a fatal, genetic neuromuscular disorders that manifests as progressive muscle wasting. Although there has been enormous progress in the studies of the molecular mechanism of muscular dystrophy, there is still no cure. Cell-based therapy is a promiseful option. This review will focus on the present status of cell-based therapy. Myoblast transfer therapy is hindered by minimal distribution of cells after injection, immune rejection, and poor cell survival. The drawback of bone marrow-derived stem cell transplantation is the low efficiency of transdifferentiation. Compared with them, the injection of postnatal muscle-derived stem cells (MDSC) results in a superior regeneration of dystrophin-expressing myofibers.

Animals↗
PubMed1991

The ability of the epithelium of diencephalic origin to differentiate into cells of the ocular lens.

After the discovery that in adult salamanders following lentectomy a new, functional lens develops by transdifferentiation (cell-type conversion) of previously depigmented epithelial cells of the iris (Wolffian lens regeneration), this phenomenon has been intensively studied by various experimental approaches. During the last two decades it was shown that pleiomorphic aggregates of atypical lens cells (lentoids) differentiated in reaggregates of dissociated cells of the chick neural retina and in spread cell cultures of the pigmented epithelium of the iris and retina, of the neural retina and the pineal gland of the chick embryo. The neural retina of human fetuses and adults also displayed this capacity. We showed that lentoids developed at a low incidence in renal isografts of rat embryonic shields or isolated embryonic ectoderm and of lentectomized eyes of rat fetuses, as well as in organ cultures of rat embryonic shields in chemically defined media. The addition of transferrin significantly increased the incidence of differentiation of lentoids in explants. In both renal isografts and explants in vitro a continuous transformation of retinal epithelial cells into atypical lens cells was observed. In renal isografts lentoids were also observed to originate from the ependyma of the brain ventricle. All tissues having the capacity to convert into lens cells belong to the diencephalon in a broad sense. Evolutionary aspects of this feature are discussed.

Animals↗
PubMed1991

Cells with neuroendocrine features in regenerating human liver.

Regeneration of liver tissue in man after submassive necrosis is reflected by replicating features in hepatocytes, and by a remarkably increased number of bile duct structures that are thought to transdifferentiate into true functioning hepatocytes. Similar to the bile ductule-related "oval cells" in rats, human bile ductular cells may therefore serve as "facultative stem cells" that become activated when hepatocyte regeneration is insufficient or inhibited. Our recent demonstration of neuroendocrine features in proliferating bile ductules in cholestatic liver disease prompted us to perform a similar immunohistochemical and electron microscopical study on regenerating human liver tissue after submassive liver necrosis. In the earliest stages of regeneration, bile ductular cells and small, singular cells in the periportal area expressed chromogranin-A and contained dense-cored, secretory granules. It is tempting to speculate that the scattered singular cells represent the human equivalent of the bipotential progenitor cells in the rat. In later stages of regeneration, these singular cells were no longer evident, suggesting their differentiation into other cell types. In these cases, neuro-endocrine cells corresponded to proliferating bile ductules and to scattered, typical hepatocytes, located near portal tracts and in regenerating nodules. In all cases, proliferating bile ductules displayed the neural cell adhesion molecule (NCAM). These data further support our hypothesis that the substance(s) produced in the dense cored secretory granules may play a role in the growth and/or differentiation of liver cells through an autocrine and or paracrine pathway.

Antibodies, Monoclonal↗
PubMed1988

Immunocytochemical localization of liver-specific proteins in pancreatic hepatocytes of rat.

Hepatocytes are induced in the pancreas of rats maintained first on a copper-deficient diet for 8 weeks and then on normal rat chow. These cells are morphologically identical to parenchymal cells of the liver. These hepatocytes contain two liver-specific proteins: carbamyl phosphate synthetase I, a mitochondrial matrix protein that participates in the conversion of ammonia to carbamyl phosphate; and urate oxidase, an enzyme that catalyzes the oxidation of uric acid to allantoin. In addition, we also present evidence indicating that dietary administration of ciprofibrate induces peroxisomal beta-oxidation pathway enzymes, while the levels of catalase are unaltered in pancreatic hepatocytes. These observations along with the previously published results further establish the identity of pancreatic hepatocytes to parenchymal cells of liver and clearly indicate that transdifferentiation of pancreatic cells to hepatocytes is associated with activation of several liver-specific genes.

Animals↗
PubMed1988

[The effect of methionine enkephalin, leucine enkephalin and the hexapeptide, dalargin on the morphology of cultured neurons].

Cell cultures derived from brain, ganglion trigeminale or retina of 5- and 9-day-old chick embryos and from brain stem or hippocampus of 16-18 day-old fetal rats were treated with Met5-, Leu5-enkephalin, or Dalargin--a synthetic hexapeptide structurally related to Leu5-enkephalin--and evaluated morphologically. The treatment of the nervous tissue cultures with the peptides markedly affected their growth pattern. Aggregates of glial and neuronal cells were surrounded by flat cells forming monolayer network structures. In cultures of brain from 5 day-old chick embryos the proliferation of the cells was significantly stimulated. No growth of neurites was observed. It is discussed that the tested Enkephalins and in the same way the Dalargin may play an important role in the early neuronal development. Their activity in phase 0 and phase 1 of the life history of nerve cells indicates aspects of temporary peptide influences. Excess of glial cells caused by the tested peptides did not enhance neuronal differentiation. The transdifferentiation of developing receptor cells into ependymal cells during the adaptation process in retina cultures as a special effect of Dalargin is discussed. The present findings suggest that the influence of (opioid) peptides in vitro may be detected morphologically and that nervous tissue culture is a valuable tool for differentiating neuronotrophic neurite-promoting and neurotoxic drug effects.

Animals↗
PubMedDate not supplied

[Cultivation of the retinal pigment epithelium in the cavity of the lentectomized eye of newts].

A study was made of proliferative activity and transdifferentiation of the cells of retinal pigment epithelium (RPE) cultivated in the cavity of the lensectomized eye of adult newt. Implantation of the newt RPE together with vascular membrane and scleral coat resulted in the regeneration of retina. In this process the character of changes in the proliferative activity of RPE and differentiation of retinal cells were the same as in the regeneration of retina in situ. RPE implanted with the vascular membrane alone, despite a high level of proliferation during the first ten days of cultivation, no differentiated retina was formed. Possible causes of these differences are discussed, and the comparison is made of the data obtained with those on RPE cultivation in vitro. After lens removal, with RPE implants present in the eye cavity, in addition to the regenerated lens, 2-3 extra lenses and retina were formed from the cells of the inner layer of the recipient's dorsal iris. Also some cases were revealed of lens formation from the cells of ventral iris. With a complete detachment of the recipient's retina (an after-effect of transplantation) a second differentiated retina regenerated in situ from the recipient's RPE cells.

Animals↗
PubMed1984

Histology of human conjunctival transplantation.

The technique of conjunctival transplantation has proven very successful in reestablishing an intact ocular surface in patients with severe ocular surface disease in whom conventional treatment has failed. We present follow-up on the histology of the transplanted conjunctival tissue in four alkali-burned patients who underwent penetrating keratoplasty 3-28 months following conjunctival transplantation. The corneal button was re-epithelialized in all patients. The fate of the transplanted tissue agreed with experimental observations made in the rabbit model, i.e., under areas of vascularization and inflammation, the transplanted tissue resembled conjunctiva with numerous goblet cells and 3-4 cell layers of nonkeratinized, stratified epithelium. In one patient, a definite "transition zone" from conjunctival to corneal appearing epithelium was seen in an area with minimal inflammation and vascularization, again confirming the animal results showing that transdifferentiation of conjunctival to corneal epithelium can occur.

Adult↗
PubMed1983

Lentoidogenesis from neural retina cells in culture is affected by interactive relationships between different cell types.

By centrifugation in a Percoll gradient, two cell fractions were separated from cell populations harvested from 8-day cultures of neutral retina cells of 3-5-day-old quail embryos. The heavy (H-) fraction contained mostly N-cells, which are considered to be putative neuronal cells, while the light (L-) fraction contained both E-cells, putative retinal glial cells, and N-cells. Determination of choline acetyltransferase activity in both fractions suggested that this enzyme is predominantly localised in N-cells. After replating the separated L-fraction for further culturing, frequent lentoidogenesis occurred from clusters of N-cells which, though few in number, were included in this fraction. Addition of H-fraction to L-fraction cells caused a significant increase in lentoidogenesis up to a ratio of N- to E-cells of 3:1. However, addition of excess H-fraction cells beyond this ratio inhibited lens differentiation. This difference in the expression of lens phenotypes resulting from the different ratios of H- and L-fraction was confirmed by monitoring the level of delta-crystallin in cultures. These results are discussed in the light of interactive relationships between N- and E-cells in the transdifferentiation of neural cells into lens in cell culture.

Animals↗
PubMed1980

On the role of germ cells in planarian regeneration. II. Cytophotometric analysis of the nuclear Feulgen-DNA content in cells of regenerated somatic tissues.

Previous findings by our group have shown how primordial male germ cells take part in regenerative blastema formation in planarians by migrating to the wound. The role of these cells in rebuilding transected tissues has been investigated in a population of Dugesia lugubris s.l. which is particularly suited for our purpose. In fact, these planarians provide a clear karyological marker to distinguish diploid male germ cells (2n = 8) from tryploid embryonic or somatic cells (3n = 12). In this study we employed the cytophotometric analysis of the nuclear Feulgen-DNA content in order to distinguish non-replicating male germ cells from reserve and somatic cells. The Feulgen-DNA content in cells from the gonad-free caudal area was measured after complete regeneration. Most non-replicating cells (94-95%) were found to have a DNA amount typical of cells previously estimated as triploid. Some (5-6%) nuclei containing a DNA amount typical of cells previously estimated as diploid male gonia were also found. These findings seem to support the view that primordial male germ cells also participate in rebuilding somatic tissues according to the field influence they encounter during regeneration. The possibility that metaplasia (or cell transdifferentiation) may occur in planarians is finally discussed.

Animals↗
PubMed1980

[Cytologic aspects of cell determination in the primitive (Hensen's) knot].

The avian primitive (Hensen's) knot is the main center of invagination and final determination of endodermal and mesodermal cells at gastrulation. At stages when the primitive streak is lengthening, cells in the primitive knot have the widest morphogenetic potencies and an outstanding ability for neural induction among other parts of the blastoderm. This labile state of the cells is characterized cytologically by an increased catabolism, expressed as an intensified decomposition of the intracellular yolk and increased autophagocytosis. In some places, the partly digested yolk is excreted from the cells and the marker-enzyme of lysosomes--acidic phosphotase--appears in the intercellular space. Some cells perish, and their debris are absorbed by neighbouring cells. The length of the intercellular contact is decreasing. Thus, the period of cell determination is characterized cytologically as a critical period, after P.G. Svetlov, with high injury and decreased regulatory activity. Individualization of the germ layers proves to be the beginning of a new developmental phase and at the cellular level it possesses some signs of transdifferentiation.

Animals↗
PubMed1980

On the role of germ cells in planarian regeneration. I. A karyological investigation.

Specimens from a polyploid biotype of Dugesia lugubris s.l. were used to clarify the role and fate of germ cells during planarian regeneration. These specimens provide a useful karyological marker because embryonic and somatic cells (3n = 12) can be easily distinguished from male (2n = 8) and female (6n = 24) germ cells by their chromosome number. We succeed in demonstrating how primordial germ cells participate in blastema formation and take part in rebuilding somatic tissues. This evidence was obtained by cutting each planarian specimen twice at appropriate levels. The first aimed to induce primordial germ cells to migrate to the wound. The second cut was performed after complete regeneration and aimed to obtain a blastema from a cephalic or caudal area devoid of gonads. A karyological analysis of mitotic cells present in each blastema obtained after the second cut provided evidence that cells, originally belonging to the germ lines, are still present in somatic tissues even months after complete regeneration. The role of primordial germ cells in planarian regeneration was finally discussed in relation to the phenomenon of metaplasia or transdifferentiation.

Animals↗
PubMed1994

Origin of spindle-shaped cells in Kaposi sarcoma.

Adult skin microvascular endothelial cells derived from new born foreskin were grown and maintained in tissue culture with and without dibutyryl cyclic AMP (DC-AMP) and isobutyl methyl xanthine (IMX). Whereas in the presence of DC-AMP and IMX, the cells showed the typical cobblestone appearance of endothelium, in the absence of these agents the cultured cells permanently converted to a spindle-shaped configuration. Because this phenomenon of transdifferentiation also occurs in the presence of specific cytokines, the profile of which is notoriously altered in acquired immunodeficiency syndrome (AIDS), the findings support the concept that in Kaposi sarcoma the spindle-shaped cells derive from dysfunction in the microvascular environment.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Induction of a serotonergic and neuronal phenotype in thyroid C-cells.

We have investigated whether rat thyroid C-cells can acquire a phenotype similar to serotonergic neurons. C-cells are neural crest derived endocrine cells with some intrinsic neuronal and serotonergic properties. A relatively simple isolation scheme yielded cultures of about 50% initial purity, as measured by fluorescence activated cell sorting. These enriched C-cells could extend neurites up to 550 microns on a laminin-containing substratum in the presence of NGF. The cultured C-cells expressed neurofilaments and this expression was enhanced by NGF treatment. The C-cells also expressed two markers of the sympathoadrenal neural crest lineage, the mammalian achaete scute homolog-1 (MASH-1) transcription factor, and the B2 cell surface antigen. Interestingly, MASH-1 was not detectable after the C-cells were placed in culture, which is consistent with neuronal differentiation, since MASH-1 is only expressed in neuronal progenitors prior to differentiation. We then demonstrated that C-cells possess the fundamental features of serotonergic neurons: synthesis and secretion, uptake, and feedback control. The enriched C-cells, as well as the CA77 C-cell line, showed 5-HT immunostaining, expression of tryptophan hydroxylase mRNA, 5-HT1B autoreceptor mRNA, and 5-HT transporter mRNA and activity. NGF greatly induced 5-HT transporter activity as determined by sensitivity to sertraline, a selective 5-HT reuptake inhibitor. Based on these results, we propose that thyroid C-cells are derived from a vagal sympathoadrenal progenitor, similar to serotonergic enteric neurons, and can undergo neuronal transdifferentiation. Hence, these cells should provide suitable and convenient models for molecular and cellular studies on serotonergic neurons.

Animals↗