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PubMed2000

Identification and cloning of a human urea transporter HUT11, which is downregulated during adipogenesis of explant cultures of human bone.

Bipotential cells in human trabecular bone explant cultures that express osteoblast characteristics are able to undergo adipogenesis in the presence of 3-isobutyl-1-methylxanthine plus dexamethasone (Nuttall et al. [1998] J Bone Miner Res 13:371-382). The initial studies of these bipotential cells in explant cultures have been extended to examine differential gene expression during osteoblast/adipocyte transdifferentiation. Using differential display, we have identified a gene expressed in trabecular bone explant cultures that is downregulated as these cells differentiate from an osteoblast to an adipocyte phenotype. Homology searching identified this gene as the human urea transporter HUT11. The expression and downregulation of HUT11 have been observed in multiple patient bone explant cultures. The size of the bone explant-derived HUT11 mRNA is approximately 4.4 kb, which is identical to the largest splice variant reported. In this article, we report the cloning and sequencing of this gene from primary human osteoblasts. In addition, we report tissue distribution for the bone explant-derived form of HUT11 mRNA and show a reciprocal relationship between the expression of HUT11 and the nuclear hormone receptor peroxisome proliferator-activated receptor gamma 2, which is a marker of adipocyte differentiation. Because the control of osteoblast/adipocyte transdifferentiation is unknown, selective downregulation of HUT11 during adipogenesis suggests that HUT11 expression may be a marker of the switch from an osteoblast to an adipocyte phenotype. Understanding the role of HUT11 in osteoblasts may provide insights into the mechanism controlling osteoblast and adipocyte differentiation.

1-Methyl-3-isobutylxanthine↗
PubMed2001

Morphologic conversion of a neuroblastoma-derived cell line by E6-mediated p53 degradation.

Neuroblastoma-derived tumor cells, unlike cells from other tumor types, characteristically express a wildtype but cytoplasmically sequestered p53 protein. To ascertain whether the p53 in these cells retained any physiological activity, we inactivated it in SK-N-SH cells, a neuroblastoma-derived cell line, by introducing the human papilloma virus type 16 E6 expression plasmid. Parent SK-N-SH cell cultures are composed of two cell types exhibiting characteristic morphologies designated neuroblastic (N-type) or substrate-adherent fibroblastic (S-type) cells, both of which have been shown to spontaneously transdifferentiate or interconvert. We report here that down-regulation of p53 resulted in conversion of SK-N-SH cells to the substrate-adherent fibroblast-like S-type cells. The morphologic conversion was accompanied by a loss of neurofilament expression, a marker for the neuronal N-type cells, an increase in the expression of vimentin, and a lack of responsiveness to retinoic acid-induced neuronal differentiation. Importantly, we did not observe N-type cells in the E6-transfected cell population, suggesting that they were incapable of transdifferentiating to the N-type morphology. We also tested the ability of these E6-transfected S-type cells to form colonies in soft agar and observed a markedly reduced capacity of these cells to do so when compared with the parent and mutant E6-transfected cells. These results suggest that p53 is required for the maintenance of the neuroblastic tumorigenic phenotype.

Agar↗
PubMed2001

Morphostats: a missing concept in cancer biology.

The role of specific morphogens is well established in the determination of body plans in development. A variety of morphogens have been identified; others are suspected. Pathways have been delineated. In complex tissues, the ability to maintain fidelity of microarchitectural structure is crucial. Microarchitecture is a consequence of relationships among cells, not a function of single cells. Epithelial layers, in particular, are able to maintain their microarchitecture with remarkable accuracy over many decades despite recurrent damage, regular cell turnover, and complexity of structure. Nonetheless, metaplasia and transdifferentiation (change in tissue structure without cell dysplasia) do occur, suggesting that there is the possibility of loss of control or change of control of the microarchitecture. A strong inference to be derived from the above is that there are control systems and molecules and that these are derived from cells that are outside, but plausibly adjacent to, the respective epithelia. It is postulated is that there are morphogen-like controller molecules with morphogen-like functions in adult epithelial tissues. These are responsible for the maintenance of normal tissue microarchitecture. Because the function of these putative molecules is maintenance of tissue structure, I have chosen to call them morphostats by analogy with morphogens. It seems plausible that morphostats and morphogens may constitute overlapping families of molecules. Evidence for the existence of morphostats can be derived from a variety of in vivo and in vitro data and from studies of normal tissue, precancer, and cancer, including: (a) the existence but rarity of metaplasia and transdifferentiation; (b) the fact that metaplasias are multicentric and are only one step from normal but do not show any consistent epithelial mutation; (c) the genesis of animal cancers by simple transplantation of tissues into the wrong environment and the evidence that epithelial mutation is not a feature of such transplantation carcinogenesis; (d) the fact that carcinogenesis occurs frequently at the junctions of different epithelial types, e.g., squamocolumnar junctions in gastrointestinal and genital tracts; (e) the fact that cancer-associated fibroblasts can stimulate proliferation in transformed cells but not influence normal cells; and (f) the failure to grow most epithelial organs in a fully differentiated structural pattern in monolayer culture. It is suggested that morphostats may function like morphogens inasmuch as they may act via a diffusion gradient from source mesenchymal cells and provide architectural instruction for complex adult epithelia. Morphostats may influence architecture via control of cell adhesion, apoptosis, and proliferation. Some specific predictions follow from this hypothesis, most notably, a new two-hit model of cancer: one mutation in an epithelial cell resulting in disruption of cell function and structure (e.g., dysplasia); and the other in a mesenchymal or other supporting cell resulting in disruption of tissue microarchitecture. The corollary of this is that there will be mesenchymal mutations producing microarchitectural abnormalities without epithelial dysplasia and vice versa. Disruption of the functions of morphostats may result in a variety of abnormalities. Such disruption may be a key event in carcinogenesis.

Animals↗
PubMed2001

[A human pluripotent stem cell in the blood of adults: towards a new cellular therapy for tissue repair].

The presence in normal adult man of stem cells sharing the properties of embryonic stem cells opens new avenues for basic and therapeutic research. We describe a stem cell present in normal adult human blood, probably able to give rise to the "reserve" stem cells in charge of repair, present in different organs. These monocytoid circulating cells are able to transdifferentiate into several cell types. In normal man, they are almost quiescent and are strictly controlled by a special subpopulation of T lymphocytes. In diseases such as fibrosis and chondrosarcoma, these cells proliferate and the differentiated cells escape T lymphocyte control. As a consequence, these cells accumulate, giving rise in vitro to a tissue which evoke the lesions characterizing the disorder of the patient, showing spontaneously their pluripotentiality. Neural cell markers are present in this migrating cell, suggesting that pluripotent stem cells present in adult man may derive from the neural crest. These circulating cells could offer a source of stem cells for cellular and gene therapy provided the normal cells could be expanded, their transdifferentiation directed and the control by T lymphocytes maintained.

Adult↗
PubMed2002

Adult corneal limbal epithelium: a model for studying neural potential of non-neural stem cells/progenitors.

Recent studies suggest that tissue-specific stem cells possess much wider potential for differentiation than previously thought and can, in some instances, even cross germ layer boundaries. However, information is lacking regarding the efficiency and the fidelity of their differentiation along heterologous lineages. To address these issues of transdifferentiation, we have analyzed the heterologous potential of stem cells within the same germ layer. We report the neural potential of cells isolated from the limbal epithelium of the adult cornea. Limbal epithelium, which, like the neuroepithelium, is ectodermally derived, participates in the regeneration of cornea throughout life. We have observed that limbal epithelial cells, when removed from their niche and cultured in the presence of mitogens, begin to express neural progenitor markers. Based on the self-renewal property, it is likely that the nestin-positive progenitors are derived from limbal stem cells rather than transit-amplifying (TA) cells that have limited proliferating potential. In differentiation conditions, a subset of these cells acquire neural morphology and express transcripts and proteins specific to neurons and glia, suggesting their differentiation along neural lineage. The acquisition of neural properties is regulated by BMP signaling. Neural differentiation of these cells is also observed upon heterotopic transplantation. Investigation of functional differentiation of cells by electrophysiological analysis reveals properties consistent with the presence of glia that are influenced by extracellular cues. However, similar analyses coupled with Ca(2+) imaging suggest an incomplete differentiation of limbal epithelial-derived neural progenitors into neurons in the condition studied. Our study, therefore, draws attention toward the necessity for rigorous characterization of transdifferentiation and offers a model for characterizing neural potential of heterologous stem cells/progenitors.

Animals↗
PubMed2004

Transforming growth factor-beta-induced transition of fibroblasts: a model for myofibroblast procurement in tissue valve engineering.

BACKGROUND AND AIM OF THE STUDY: The selection of a suitable cell type for scaffold seeding, its isolation and adequate expansion in vitro remains a major challenge in tissue valve engineering. The study aim was to establish a model for efficient procurement of myofibroblasts for in-vitro seeding using fibroblasts as progenitor cells. METHODS: Dermal and arterial mesenchymal cells from human (hDMC1.1 and hAMC1.1) and sheep (sDMC1.1 and sAMC1.1) were isolated by sequential culture. Cell isolates were characterized by stringent criteria based on morphology, immunocytochemistry using antibodies to vimentin, cytokeratin, prolyl 4-hydroxylase, smooth muscle alpha-actin (alpha-SMA) and smooth muscle myosin, and by Western blotting for alpha-SMA and N-cadherin. Cultures with less than 10-20% alpha-SMA-positive cells were considered to be fibroblastic. Cells were subsequently transdifferentiated with the cytokine transforming growth factor-beta1 (TGF-beta1) during five days, and then evaluated morphotypically, by immunocytochemistry, and by Western blotting. The metabolic and functional properties of TGF-beta1-treated and untreated colonies were compared by measuring the expression of extracellular proteins (collagen type 1 and tenascin-C) and by a collagen matrix contraction assay. RESULTS: TGF-beta1 successfully transformed both human and sheep fibroblasts to metabolically active and functional myofibroblasts based on stringent criteria for myofibroblast characterization. Alpha-SMA positivity of 100% was obtained in all cases (hDMC1.1, hAMC1.1, sDMC1.1, and sAMC1.1) after transformation compared to less than 50% in the non-transformed state (hAMC1.1, 17%; hDMC1.1, 10%; sAMC1.1, 43%; and sDMC1.1, 30%). This observation was further supported by increased contractility and an up-regulation of extracellular protein production in transdifferentiated cells. CONCLUSION: Untreated arterial cell isolates were, at best, less than 50% alpha-SMA-positive. By allowing procurement of high densities of myofibroblasts in a relatively short time, the model was seen to be a potentially useful tool in tissue valve engineering, at least in investigations using autologous cells in the sheep model.

Actins↗
PubMed2004

[Reprogramming of adult human pancreatic duct cells as functional beta cells].

The most plausible therapy for type I diabetes is restoration of the functional beta cell mass, as is proven by the clinical success of transplantation of donor beta cells. This approach, however, is very limited by the low number of donor organs available. One solution for this shortage would be well controlled generation of beta cells for transplantation. The bona fide beta progenitor cell is not known yet. As duct cells of the adult human pancreas show a high degree of plasticity, they were genetically manipulated to transdifferentiate into beta cells. The transcription factor neurogenin 3, a master switch of embryogenesis of the endocrine pancreas, was ectopically expressed in adult human pancreatic duct cells. Neurogenin 3 induced a phenotypic shift by activation of a series of endocrine marker genes, among which insulin. However, the number of insulin-producing cells and the amount of insulin per cell were low and the transdifferentiated duct cells remained glucose insensitive. A strategy for optimizing the reprogramming of adult human duct cells to beta cells is proposed.

Cell Differentiation↗
PubMedDate not supplied

[Multipotent and stem cells in the developing, definitive, and regenerating vertebrate eye].

This is a review of the experimental studies on the vertebrate retina neurogenesis. Data are provided on the distribution and localization of multipotent and stem cells in the developing, definitive, and regenerating eye. At the early stages of retina development, the neuroepithelial cells divide synchronously, thus leading to the accumulation of a certain number of the retinal rudiment cells. Synchronous divisions precede the asynchronous ones, when the differentiation of the retinal cells is initiated. The neuroepithelial cells are multipotent: the neuroblast is a source of the cells of different types, for example, neurons and glial cells. The proliferating multipotent cells are preserved in the ciliary-terminal zone of the retina of amphibians, fish, and chickens during their entire life. The differentiated pigment epithelium cells also proliferate in this area of the eye. The multipotent cells of the retinal ciliary-terminal zone and cells of the pigment epithelium in the eye periphery provide for the growth of amphibian and fish eyes during the entire life of these animals. In adult mammals, clonable and self-renewable cells were found among the pigmented differentiated cells in the ciliary folds. In a culture, the stem cells form spheroids consisting of depigmented and proliferating cells. Upon transdifferentiation, the cells of spheroids form rods, bipolar cells, and ganglionic and glial cells, thus suggesting the possible regenerative potencies of the stem cells in the ciliary body of the mammalian eye. The main event of retinal regeneration in newts is the transdifferentiation of the pigment epithelium cells. The results of comparative analysis suggest that the stem cells of the ciliary body in the mammalian eye and pigment epithelium cells in lower vertebrates exhibit similar potencies and use similar mechanisms during the formation of the cells of the neural series.

Animals↗
PubMed2005

Exact relevance of bone marrow cells in the healing process after myocardial infarction: analysis with a murine model of bone marrow cell transplantation.

BACKGROUND: Cellular cardiomyoplasty has created new possibilities in cardiac regeneration. Several cell types can be used in the procedure, such as skeletal myoblasts and bone marrow cells. Recent publications have suggested that bone marrow cells may be excellent candidates due to their pluripotency, but their actual role in cardiac regeneration is unknown. OBJECTIVE: To evaluate the exact physiological role of bone marrow cells in the healing process after myocardial infarction. METHODS: A mouse bone marrow cell transplantation model was used in which transplanted cells were easily detectable by immunohistochemistry. Chimeric mice were subjected to myocardial infarction by ligation of the left descending coronary artery. After one month, the mice were sacrificed and the scars were analyzed. RESULTS: Transplanted bone marrow cells were detected in the scars and these cells seemed able to transdifferentiate into endothelial cells, but no transdifferentiation into cardiomyocytes occurred. This mechanism of regeneration was dismissed because only 2% of the vessels in the scars were positive for transplanted cells. CONCLUSIONS: Bone marrow cells might be involved in myocardial healing, but this physiological mechanism is insufficient to allow correct regeneration.

Analysis of Variance↗
PubMed2006

Physiological and pathological consequences of identification of very small embryonic like (VSEL) stem cells in adult bone marrow.

Bone marrow (BM) contains a population of self-renewing hematopoietic stem cells (HSC) that give rise to cells from all hemato-lymphopoietic lineages. The concept that HSC could also be plastic and be able to transdifferentiate into stem/progenitor cells for different non-hematopoietic tissues became one of the most controversial issues of modern stem cell biology. Accumulating experimental evidence suggests that contribution of BM-derived stem cells to organ/tissue regeneration could be explained not by plasticity (transdifferentiation) of HSC but rather by the presence of non-hematopoietic stem cells in BM. In this review new evidence will be presented, that adult BM contains a small population of pluripotent very small embryonic-like (VSEL) stem cells. These cells are deposited in BM early during ontogenesis and could be mobilized from BM and circulate in peripheral blood during tissue/organ injury in an attempt to regenerate damaged organs. However, if these cells are mobilized at the wrong time and migrate to the wrong place they may contribute to the development of several pathologies, including tumor formation.

Adult↗
PubMed2006

[Screening of differentially expressed genes in rats with cardiomyopathy after bone marrow mesenchymal stem cell transplantation].

OBJECTIVE: Earlier studies have confirmed that mesenchymal stem cells (MSCs) can transdifferentiate into myocytes and improve heart function in 2 weeks. But the mechanism is not clear. In this study, the mechanism of improvement of heart function after transplantation of MSCs was examined with suppression subtractive hybridization (SSH). METHODS: MSCs were isolated from thighone and tibia of Wistar rats, purified by adhesion-screening method, and expanded in vitro. Intraperitoneal injection of doxorubicin (at 2.5 mg/kg/time and total doses of 15 mg/kg) established cardiomyopathy models. MSCs were transplanted into cardiomyocytes. The differential genes between tester (rats with cardiomyopathy that were injected with MSCs) and driver (rats with cardiomyopathy that were injected with equivalent volume of culture medium) were screened with suppression subtractive hybridization. RESULTS: After 4 weeks of intraperitoneal injection of doxorubicin, left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) decreased by 26.48% and 40.61%, respectively (P < 0.01), as compared with those of normal group. Cardiomyopathy model was established successfully. And the heart function of the rats with cardiomyopathy was significantly improved after transplantation. Sixteen gene fragments were detected, and 12 of them were up-regulated in testers. They were rattus norvegicus mitochondrial BN/SsNHsdMCW, rattus norvegicus strain mitochondrial F344 X BN F1, rattus norvegicus mitochondrion H(+)-ATP synthase alphase subunit (Atp5al) mRNA, rattus norvegicus BHE/Cdb tRNA-Lys gene, rat mitochondrial H(+)-ATP synthase alpha subunit mRNA, rattus norvegic (wild-caught animal) complete mitochondrial genome, rattus norvegic clone BB.1.4.1 unknown Glu-Pro dipeptide repeat protein mRNA, Arabidopsis thaliana transgenic line C DNA, rat mitochondrial ATP synthase beta subunit mRNA, rattus norvegic mitochondrial genome, rat cardiac troponin T mRNA and rat mRNA for beta-globin. Four gene fragments were down-regulated in testers. They were rat mRNA for sarcomeric mitochondrial creatine kinase, rat mRNA for ribosomal phosphoprotein P2, rat alpha-crystallin B chain mRNA and rattus norvegicus NADH-ubiquinone oxidoreductase Fe-S protein 7 mRNA. CONCLUSION: The expression of the genes relating to mitochondrial synthesizing and contracting proteins synthesizing increased after MSC transplantation. The genes might enhance energy synthesis and promote MSC transdifferentiate into myocytes, and then improve heart function of rats with cardiomyopathy.

Animals↗
PubMed1991

Morphological development and fate of the mouse mesonephros.

A study has been made of the development of mesonephric tubules in the mouse to investigate the possible transdifferentiation of tubule epithelial cell to gonadal somatic cells and/or adrenal cortical cells. Immunohistochemical localisation of laminin was carried out to study the development of basal laminae. Cells at the ventral aspect of mesonephric tubules did not show an epithelial phenotype during the period of somatic cell population of the gonadal blastema; a basal lamina appeared ventrally only after this period. Therefore, it is not necessary to postulate transdifferentiation of these cells.

Adrenal Cortex↗
PubMed1985

Presence and regulation of tyrosinase activity in human neuroblastoma cell variants in vitro.

The human neuroblastoma cell line SK-N-SH comprises cells that undergo morphological and biochemical interconversion between a primitive sympathoblast and a variant, epithelial-like cell type which does not express the neuronal characteristics of the SK-N-SH cell line. Since neural crest cells, from which neuroblastomas are presumed to arise, can undergo transdifferentiation in culture from a neuronal phenotype into other cellular phenotypes, particularly into neurilemmal cells and melanocytes, the present study was undertaken to determine whether this capacity is preserved in malignant cells of the peripheral nervous system. Activities for tyrosinase, a melanocyte marker enzyme, and 2':3'-cyclic nucleotide phosphohydrolase, a Schwann-cell marker enzyme, were measured in clones of the two cell types. While no significant differences in 2':3'-cyclic nucleotide phosphohydrolase activity were measurable, tyrosinase activity was detectable only in the flattened neuroblastoma variant cell lines and was comparable to that in some human melanoma cell lines. The tyrosinase activity in neuroblastoma cell variants increased with cell density and was significantly elevated by melanocyte-stimulating hormone and 8-bromo-cyclic adenosine monophosphate, similar to that seen in melanoma cells in culture. Thus, our findings show that human neuroblastoma cells can undergo bidirectional transdifferentiation in vitro between a neuronal and a melanocyte phenotype, possibly reflecting a process which occurs in the patient.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMedDate not supplied

[Inductive effect of the eye tissues of adult clawed toads on the gastrula ectoderm].

The inducing influence of adult eye tissues on the early gastrula ectoderm was studied in vitro. Both retina and pigment epithelium induced in the early gastrula ectoderm similar spectra of cell types, including nervous tissue, retina, pigment epithelium, lentoids, ectomesenchyme, and melanophores. It is suggested that the correspondence of these cell types with those arising at a spontaneous transdifferentiation of the isolated retina and pigment epithelium cells in vitro or at the induction of the early gastrula ectoderma by archencephalic endomesoderm during the normal development can be accounted for by that in these eye cells molecular determinants appeared as a result of induction and maintaina the stability of their differentiation and their potencies to transdifferentiation in vitro being reproduced during the lifetime of these cells.

Animals↗
PubMedDate not supplied

[Radioautographic study of the cellular proliferation of retinal pigment epithelium in axolotls].

The proliferative activity of the pigment epithelium cells in the axolotl eyes was studied using 3H-thymidine in two types experiments: after the removal of lens, iris and retina and upon the cultivation of the pigment epithelium pieces in the cavity of lens-less eye. Irrespective of the operation type, the level of proliferation of the pigment epithelium cells changed regularly with respect to the time of observation. In the intact eye, the level of proliferation of the pigment epithelium cells was not high: the index of labelled nuclei equaled 0.5%, no mitoses were found. The highest values of the index of labelled nuclei (12.6-32.1%) and of the mitotic index (0.54-1.07%) were registered on the 10-20th days after the operation. After 40 days, the indices of proliferative activity of the pigment epithelium cells approached gradually those for the intact eye. The cultivation of the pigment epithelium cells in the cavity of a lens-less eye for 50 days did not result in their transdifferentiation into retina cells. The layered retina found in 7.7% of cases after the removal of lens, iris and retina could regenerate either from the cells of the retina growth zone localized in the region of embryonic split, or due to transdifferentiation of the pigment epithelium cells.

Ambystoma mexicanum↗
PubMed1981

Experimental posterior subcapsular cataracts-with special reference to 1-beta-D-arabinofuranosyl-cytosine (Ara C)-induced cataracts.

Experimental posterior subcapsular cataracts were induced by the action of 1-beta-D-arabinofuranosyl-cytosine (ara C) and vincristine sulfate (VCR) in the rat crystalline lens. Differences between these two types of cataracts observed by light microscopy were degenerative necrosis of the anterior capsular epithelial cells (in the ara C-induced cataract), and the transdifferentiation phenomenon of the lens epithelial cells (VCR-induced cataract). Transformation of the epithelial cells and subsequent abnormal cellular differentiation (transdifferentiation) could be the primary trigger in he development of cataracts.

Animals↗
PubMed1978

Developmental approaches to organ restoration.

This paper discusses the problem of applying the achievements of developmental biology to organ restoration. Experiments on artificially induced transdifferentiation as a prerequisite for organ restoration are reviewed. The advantage of using cells that start differentiation from the dedifferentated state is that they can participate in the construction of new organs. However, cell transdifferentiation is not sufficient for biomedical purposes, since the problem of construction of typically formed organs--namely, the morphogenesis of groups of differentiating cells--remains to be solved. Data, where a partial approach to typical organ restoration has been achieved are analysed. This serves as a tentative step in the application of developmental-biological approaches to the problem of organ restoration.

Amphibians↗
PubMedDate not supplied

[Cell sources, regulatory factors and gene expression in the regeneration of the crystalline lens and retina in vertebrate animals].

Over the past century extensive experimental materials have been accumulated concerning cell sources of lens and retina regeneration, successive transformations of the cells, regulatory factors, and gene expression during restitution of these eye structures. The use of nuclear and cytoplasmic markers provided convincing evidence that the removed lens is restituted from the dorsal iris cells in vivo or from embryonic cells of the pigment epithelium and retina in vitro. The removed or destroyed retina is restituted as a result of transdifferentiation of the pigment epithelium cells in amphibians, fish, birds, and mammals during embryogenesis, in larvae of some anuran amphibians, and in adult newts. Cell precursors of rods are a cell source of retina regeneration in adult fish. A subpopulation of randomly distributed cells, which are a cell source of rod formation during the normal development of the eye was found in the external nuclear layer with the use of electron microscopy and nuclear and cytoplasmic markers. These cells are not only a source of regeneration of rods, but also of cones and cells of the internal nuclear layer after destruction of the corresponding retina layers. There is a peripheral growth area in the retina of vertebrates, where multi- and unipolar cells are localized, which provide for the retina growth during ontogenesis. A paradox of retina regeneration consists in that these little differentiated cells are not a source of complete restitution of the removed or destroyed retina. They make only a small contribution to its regeneration corresponding to the growth potential of cells of this eye region, while restitution of the retina proceeds only at the expense of cells of another type of differentiation. A factor controlling the differentiated state of the cell was found in the dorsal iris during studies of lens regeneration. Removal of this factor in the early stages of cell transformations leads to the initiation of lens regeneration. The factor is not specific and was identified in many cells of vertebrates, including the pigment epithelium and limb tissues, which, as is known, may be fully restituted. Studies of gene expression during lens and retina regeneration are now at the initial stage. The greatest advances were achieved on the model of transdifferentiation of the pigment epithelium cells of chick embryos into lentoids. Expression of genes MMP115 and pP344 was established in the pigment epithelium cells, which characterize the pigmented phenotype of the initial cells. Expression of the alpha-, beta-, and delta-crystallin genes was found in the lentoids, which characterize the phenotype of regenerating structures. The gene activity appears to be switched at an intermediate stage during cell dedifferentiation. Expression of the gamma-crystallin genes during lens regeneration in adult newts is initiated after completion of dedifferentiation and cell proliferation in the dorsal iris. The genes specifically expressed in the dorsal and ventral iris and in the retina rudiment have been identified by the method of gene subtraction. Expression of homeobox-containing genes from the family of PAX genes was found during lens regeneration in adult newts and retina regeneration in adult fish. The role of growth factors (FGF) as morphogenetic factors was proved, which are involved in a yet unknown way of altering the differentiation pathway of the initial cells during formation of the neuroepithelium rudiment in chick embryos, adult newts, and fish.

Animals↗