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At least 19 recordsLinked to original sources
PubMed2026

Loss of function of ALDH3B2 transdifferentiates human pancreatic duct cells into β-like cells.

Replenishment of pancreatic β cells is key to a cure for diabetes. β cell regeneration is achieved predominantly by self-replication, especially in rodents, but it was also shown that pancreatic duct cells can transdifferentiate into β cells. How pancreatic duct cells are transdifferentiated and whether we can manipulate transdifferentiation to replenish β cell mass are not well understood. Using a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen, we found that the loss of function of aldehyde dehydrogenase family 3 member B2 (ALDH3B2) was sufficient to transdifferentiate cell line-based and human pancreatic duct cells into functional β-like cells. The transdifferentiated cells had substantially increased the expression of β cell marker genes, secreted insulin in response to glucose, and lowered blood glucose to near normal for 6 weeks after transplantation into streptozotocin-induced diabetic mice under the kidney capsule. Our study identifies a gene that could potentially be targeted in human pancreatic duct cells to replenish β cell mass for diabetes therapy.

Humans↗
PubMed2024

Loss-of-function of ALDH3B2 transdifferentiates human pancreatic duct cells into beta-like cells.

Replenishment of pancreatic beta cells is a key to the cure for diabetes. Beta cells regeneration is achieved predominantly by self-replication especially in rodents, but it was also shown that pancreatic duct cells can transdifferentiate into beta cells. How pancreatic duct cells undergo transdifferentiated and whether we could manipulate the transdifferentiation to replenish beta cell mass is not well understood. Using a genome-wide CRISPR screen, we discovered that loss-of-function of ALDH3B2 is sufficient to transdifferentiate human pancreatic duct cells into functional beta-like cells. The transdifferentiated cells have significant increase in beta cell marker genes expression, secrete insulin in response to glucose, and reduce blood glucose when transplanted into diabetic mice. Our study identifies a novel gene that could potentially be targeted in human pancreatic duct cells to replenish beta cell mass for diabetes therapy.

Journal Article↗
PubMed1992

Transdifferentiation of chicken retinal pigmented epithelial cells in serum-free culture.

A serum-free culture of chicken retinal pigmented epithelial cells has been established in order to analyse how cell-substrate interactions or environmental factors affect the process of transdifferentiation into lens cells from pigmented epithelial cells. The serum-free culture medium for chicken pigmented epithelial cells was Eagle's minimum essential medium, supplemented with chicken transferrin, soybean trypsin inhibitor and bovine insulin. Pigmented epithelial cells were able to survive and grow in the medium for longer than 2 weeks. Collagen did not promote initial cell attachment, but this material effectively supports pigmented epithelial cells to organize monolayer structure characteristics to pigmented epithelium in situ in comparison with the plastic substrate of culture dishes. The process of lens transdifferentiation of chicken pigmented epithelial cells in serum-free conditions was also enhanced with the aid of phenylthiourea and testicular hyaluronidase, which had already been known to promote the transdifferentiation of pigmented epithelial cells in the serum-supplemented condition. Typical lentoid bodies were developed after about 2 weeks of serum-free culture. Thus, we can clearly demonstrate that the chicken embryonic pigmented epithelial cells do not always require a full set of serum factors for their transdifferentiation to lens cells in vitro.

Animals↗
PubMed1991

Transdifferentiation of hypertrophic chondrocytes into osteoblasts in murine fetal metatarsal bones, induced by co-cultured cerebrum.

The fate of hypertrophic chondrocytes in 17-day-old metatarsal bones of fetal mice was studied in a culture system in which these cells were kept confined to their lacunae. Because the periosteum had been stripped off, osteoclasts could not invade the long bone and resorb the lacunar walls. The majority of the hypertrophic chondrocytes stayed alive and dedifferentiated gradually into cells with the appearance of stromal cells. When the long bones were co-cultured with pieces of cerebrum, the chondrocytes transdifferentiated into osteoblasts. We followed this process from day to day. The cells produced bone matrix that immunostained for collagen type I and osteocalcin. To exclude with certainty the possibility that the intralacunar osteoblasts had derived from remaining periosteal osteoprogenitor cells that invaded the lacunae, the long bones were pre-cultured with cytochalasin D, which inhibits cell proliferation and migration. After removal of the drug this effect persisted until after transdifferentiation had occurred. This proved that the bone matrix producing osteoblasts inside the cartilage lacunae were transdifferentiated chondrocytes. The transdifferentiation stimulating factor from brain tissue is still unknown.

Animals↗
PubMed1978

Influence of embryonic stage on the transdifferentiation of chick neural retina cells in culture.

Neural retina cells from chick embryos up to 15 days of incubation can transdifferentiate in culture into both lentoids and pigment cells. Some transdifferentiation into pigment cells but none into lentoids was found in cultures of 17-day embryonic neural retina. No transdifferentiation occurred in cultures of neural retina from embryos immediately before hatching. In general, lentoids and pigment cells develop more rapidly and in greater numbers in cultures of neural retina from the earlier embryonic stages, and lens-specific crystallins also appear earlier and accumulate in greater amounts in these cultures. Delta crystallin accumulation is much greater in transdifferentiating cultures of early embryonic neural retina, wheras alpha and beta crystallins become proportionately more prominent in cultures of late embryonic neural retina. Traces of alpha and beta but not delta crystallin are detectable in 60-day cultures of 17-day embryonic neural retina. Analogies between these results and the ontogeny of crystallin polypeptides in lens cells in vivo are discussed.

Animals↗
PubMed1992

Histamine-modulated transdifferentiation of dermal microvascular endothelial cells.

Homeostatic and inflammatory functions of skin microvessels are tightly regulated by vasoactive amines. Following stimulation with histamine, dermal microvascular endothelial cells (MEC) undergo a rapid change in phenotype (transdifferentiation) and subsequently exhibit an enhanced rate of growth. To elucidate mechanisms regulating MEC transdifferentiation, this study investigated the functional relationships among vimentin, Ca2+, and protein kinase C (PKC) in histamine-modulated dermal MEC in vitro. Distribution of vimentin and PKC in foreskin-derived MEC cultivated in a modified Iscove's medium was assessed with immunocytochemistry. Calcium ion kinetics in histamine-treated MEC were analyzed using the Ca2+ probe Fluo-3 in conjunction with interactive laser cytometry. Histamine, acting through H-1 receptors, produces a rapid (less than 100 ms) and differential elevation of free calcium in each of three cytological compartments defined by the vimentin cytoskeleton in epithelial MEC. A distinctive compartmentalized and nonuniform distribution of PKC precisely coincides with that observed for free-Ca2+ released in response to histamine. The studies reveal that histamine modulation of the MEC phenotype is associated with a rapid patterned reorganization of the vimentin skeleton. It is hypothesized that histamine induces vimentin post-translational modifications by activating a spatially localized interaction among cytoplasmic free Ca2+, PKC, and the vimentin matrix. The results further suggest that vimentin, in addition to its structural role, may participate in signal transduction and gene regulation processes in effecting MEC transdifferentiation.

Calcium↗
PubMed1992

Transdifferentiation of murine squamous vaginal epithelium in proestrus is associated with changes in the expression of keratin polypeptides.

The superficial layers of the stratified squamous epithelium of the murine vagina undergo transdifferentiation into cuboidal mucinous cells during the proestrus phase of the normal estrous cycle. In contrast to their squamous progenitor cells which have the cytoskeletal characteristics of squamous epithelium, mucinous cells express keratin polypeptides typical of simple nonstratified epithelia. Accordingly, the transdifferentiation of squamous cell into mucinous cells involves not only a change in cell morphology but also a switch in the expression of keratin polypeptides. These data indicate that the stratified squamous cells of the vagina are not terminally differentiated and their phenotype can be hormonally modulated.

Animals↗
PubMed1991

Microvessel endothelial cell transdifferentiation: phenotypic characterization.

Human dermal microvessel endothelial cells (MEC) have two basic functions: maintenance of tissue homeostasis and facilitation of inflammatory responses. The former requires that the endothelium expresses traits of an epithelium, while inflammatory reactions are associated with intimal disruption. Acute inflammation transiently alters endothelium, whereas chronic inflammation may result in vessel reorganization and MEC mesenchymalization. Foreskin MEC in vitro undergo a similar epithelial-mesenchymal modulation. In the presence of cAMP, cultivated dermal MEC exhibit the structural and functional characteristics of an epithelium. MEC grown in cAMP-deficient medium initially have a "transitional" configuration and are subsequently transformed into mesenchymal cells. If cAMP is replaced by histamine, MEC maintain a stable intermediate transitional configuration. Transitional MEC refed cAMP-supplemented medium revert to an epithelial phenotype, whereas parallel cultures fed cAMP-deficient medium are transformed into mesenchymal cells. Phenotypic modulation can be induced without cell division and thus provides a unique example of direct transdifferentiation. Our data furthermore suggest that this transdifferentiation results in the acquisition of properties usually attributed to cells of the reticuloendothelial system.

Cell Differentiation↗
PubMed1991

Molecules specific to pigment epithelial cells: expression during in situ development and in vitro lens transdifferentiation of chick embryo pigment epithelium.

The retinal pigment epithelium (PE) is a monolayer of cells and plays a vital role in the regulation of the neural retina. We prepared monoclonal antibodies directed against retinal PE cells to analyze the specificity and differentiation of these cells. Spleen cells from BALB/c mice immunized with chick embryo retinal PE cells were fused with myeloma cells. Seven independent monoclonal antibodies were obtained which specifically recognized PE cells but did not react with any other tissues examined. None of the monoclonal antibodies reacted with the choroid and skin of pigmented chicks, suggesting that these antigens were unrelated to melanogenesis. Two of the 7 antibodies reacted with the PE cells in the retina, ciliary body and iris; the remaining 5 antibodies were specific to the PE cells in the retina. In the process of in vitro lens transdifferentiation from PE cells, the distribution of an antigen detected by one monoclonal antibody changed from the cytoplasmic granules to the actin fibers and then its immunoreactivity declined. The other monoclonal antibodies did not react with the differentiated PE cells and transdifferentiated lens cells, suggesting that the antibodies might be specific to the PE cells in the differentiated state, both in vivo and in vitro. During the in situ developmental process, each monoclonal antibody began to be immunoreactive to future PE cells in the optic eye cup at various stages from 72 to 120 h. The molecules common to all types of PE cells were expressed earlier than those specific to PE cells of the retina. Future ciliary and iridial PE cells appeared to transiently express the molecules specific to the retinal PE cells before the tip of eye cup contacted the lens vesicle. These data suggest that the monoclonal antibodies established in this study are powerful probes for exploring the functions and differentiation of PE cells.

Actins↗
PubMed1992

Steroids can modulate transdifferentiation of prolactin and growth hormone cells in bovine pituitary cultures.

Fluctuations in the proportions of pituitary acidophils (cells that release GH and PRL, either separately or concurrently) have been correlated with dynamic changes in the steroid hormone milieu. Since modulation of these acidophilic subtypes can occur without appreciable alterations in the total number of acidophils, it has been proposed that GH- and PRL-secreting cells can actually transdifferentiate (gain or lose the ability to release GH or PRL). To test this hypothesis, we examined the effects of steroids on the proportions of cells that released GH, PRL, or both hormones (i.e. mammosomatotropes) in bovine pituitary cell cultures. Specifically, anterior pituitary cells from castrated males were cultured for 6 days in the absence (controls) or presence of 17 beta-estradiol, cortisol, or progesterone. Reverse hemolytic plaque assays revealed that 6.64 +/- 1.2% of all pituitary cells released GH, while 68.8 +/- 5.3% were PRL secretors in control cultures. Cortisol and progesterone induced an increment in the proportions of GH-secreting cells (10 nM cortisol, +11.7 +/- 2.4%; 1000 nM cortisol, +10.5 +/- 4.7%; 1000 nM progesterone, +2.87 +/- 1.5%) above control values while decreasing the relative abundance of cells that released PRL (10 nM cortisol, -7.6 +/- 1.7%; 1000 nM cortisol, -6.6 +/- 1.2%; 1000 nM progesterone, -5.5 +/- 1.3%) below control values. However, 17 beta-estradiol was ineffective in this regard at doses of 0.1-1000 nM. A more critical examination of the steroid-induced changes revealed that they were attributable to increases in the proportions of cells that released GH alone and both hormones simultaneously along with a concomitant decrease in the fraction that secreted only PRL. Two lines of evidence discount the possibility that these effects were due to selective cell proliferation. First, the mitotic rate of cultures (assessed by immunofluorescent detection of bromodeoxyuridine incorporation) was only about 1% of all cells in both control and steroid-treated cultures. Second, blocking cell proliferation by the addition of cytosine arabinoside (100 microM) did not inhibit the cortisol-induced augmentation of GH-releasing cells. Taken together, these results substantiate the hypothesis that acidophilic subpopulations are capable of transdifferentiation given an appropriate hormonal signal.

Animals↗
PubMed1992

Rapid acinar to ductal transdifferentiation in cultured human exocrine pancreas.

Experiments have been performed to define conditions for the primary culture of human exocrine pancreas, as a first step towards molecular reconstruction experiments of pancreatic neoplasia. Normal human exocrine pancreas was digested using collagenase and dispase and the resulting cellular aggregates were cultured in vitro. The phenotype of the digested pancreatic cells was almost exclusively acinar (amylase-positive, keratin 19 and mucin antigens-negative), yet within 4 days of culture the cells had taken on a ductal phenotype (amylase-negative, keratin 19 and mucin antigens-positive). The kinetics of these observations exclude the possibility of overgrowth of the acinar population by a ductal sub-population, and selective adherence is excluded by examination of those cells that do not adhere, which are representative of the initiating population. We interpret these data as indicating that, under the conditions of culture, the acinar cell phenotype is not stable and can transdifferentiate to a ductal phenotype. Taken together with recent data from transgenic animals, this in vitro observation has possible implications for our view of the pathogenesis of pancreatic neoplasia.

Adult↗
PubMed1992

Early and late effects of NGF may be mediated by different pathways in transdifferentiating chromaffin cells.

Nerve growth factor (NGF) causes cultured adrenal chromaffin cells to extend neurites and, after about two weeks of exposure, to 'transdifferentiate' into mature sympathetic neurons. The molecular events leading to these responses are not fully understood, but one possible mediator of NGF's actions is protein kinase C (PKC), which can be directly activated by phorbol esters, including phorbol myristate acetate (PMA). Chronic exposure to PMA mimics the early effects of NGF, that is, it elicits the outgrowth of neurites and an enhanced rate of proliferation. However, while the initial responses to NGF and PMA are similar, after 10 days in culture striking differences become apparent: (1) cells in PMA fail to differentiate into sympathetic neuron-like cells and appear to remain in a transitional state. Even after more than 5 weeks in PMA, cells appear morphologically the same as those grown in PMA for only one week; cells fail to form a dense neuritic network or to exhibit the somatic hypertrophy characteristic of sympathetic neurons. (2) Cells continue to proliferate for at least 4 weeks in PMA, while cells in NGF become postmitotic after about two weeks. (3) While NGF supports and causes the further neuronal differentiation of cells grown in PMA, PMA cannot support NGF-dependent cells. These results suggest that different second messenger systems may be operating in the early and late effects of NGF.

Animals↗
PubMed1992

Progressive stages of "transdifferentiation" from epidermal to mesenchymal phenotype induced by MyoD1 transfection, 5-aza-2'-deoxycytidine treatment, and selection for reduced cell attachment in the human keratinocyte line HaCaT.

The ability of the myogenic determination gene (MyoD1) to convert differentiating human keratinocytes (HaCaT cell-line) to the myogenic pathway and the effect of MyoD1 on the epidermal phenotype was studied in culture and in surface transplants on nude mice. MyoD1 transfection induced the synthesis of myosin, desmin, and vimentin without substantially altering the epidermal differentiation properties (morphology, keratin profile) in vitro nor epidermal morphogenesis (formation of a complex stratified squamous epithelium) in surface transplants, demonstrating the stability of the keratinocyte phenotype. 5-Aza-CdR treatment of these MyoD1-transfected cells had little effect on the cultured cells but a morphologically unstructured epithelium was formed with no indications of typical cell layers including cornification. Since prevention of epidermal strata in transplants was not accompanied by blocked epidermal differentiation markers (keratins K1 and K10, involucrin, and filaggrin), the dissociation of morphogenesis and expression of these markers argues for independently controlled processes. A subpopulation of less adhesive cells, isolated from the 5-aza-CdR treated MyoD1-transfectants, had lost most epithelial characteristics in culture (epidermal keratins, desmosomal proteins, and surface-glycoprotein Gp90) and had shifted to a mesenchymal/myogenic phenotype (fibroblastic morphology, transactivation of Myf3 and myogenin, expression of myosin, desmin, vimentin, and Gp130). Moreover, the cells had lost the ability to stratify and remained as a monolayer of flat elongated cells in transplants. These subsequent changes from a fully differentiated keratinocyte to a mesenchymal/myogenic phenotype strongly argue for a complex "transdifferentiation" process which occurred in the original monoclonal human epidermal HaCaT cells.

Animals↗
PubMed1992

Transdifferentiation of macrophages into fibroblasts as a result of Schistosoma mansoni infection.

The possibility of transdifferentiation of macrophages into fibroblasts which could be at the origin of fibrotic tissue in schistosome-infected mice was studied using immunocytochemical techniques. Macrophage cell samples extracted from the peritoneal cavity of schistosome-infected mice were fractionated on a Percoll gradient. The cultures were purified by treatment with a trypsin solution to eliminate any fibroblasts possibly collected along with the macrophages. Immunocytochemical methods were then used to characterize the cells at different points in time. The fibroblastic property of the morphologically transformed cells was confirmed by their positive labeling with the anti-procollagen antibody. However, these cells still possessed the mac-1 and mac-2 antigens which characterize the monomacrophage line.

Animals↗
PubMed1978

'Transdifferentiation' of chicken neural retina into lens and pigment epithelium in culture: controlling influences.

The in vitro transdifferentiation of chicken embryo neural retina into pigment epithelium and lens cells was investigated under a variety of experimental conditions. Our findings suggest that some aspects of the phenomena are a function of medium composition and volume, whereas others depend upon conditions which develop during culture growth. Before melanin is visible, potential pigment cells are recognized as foci within epithelial sheets which remain in contact with the dish. The final area occupied by colonies of potential pigment cells is directly proportional to bicarbonate concentration. Low total medium volume also favours formation of potential pigment cells. In contrast the extent of cells other than potential pigment cells is not related to bicarbonate and is favoured when the volume of medium is large. Accumulation of melanin within the potential pigment cell colonies is suppressed when cells are crowded together. Lentoid bodies are formed from cells which are distinct from potential pigment cells and arise in crowded situations, in association with multilayering. Another type of structure superficially resembling a lentoid is derived from cell aggregates formed during the initial establishment of cultures. The survival of these 'aggregate bodies' is inversely related to bicarbonate concentration. Crystallin content is unrelated to lentoid numbers. The results provide the basis for a new hypothesis concerning cytodifferentiation in this system.

Animals↗
PubMed1992

Fate of ciliated epidermal cells during early development of Xenopus laevis using whole-mount immunostaining with an antibody against chondroitin 6-sulfate proteoglycan and anti-tubulin: transdifferentiation or metaplasia of amphibian epidermis.

Xenopus embryonic epidermis changes its cellular composition during development: the appearance of ciliated epidermal cells before hatching is a remarkable characteristic. In this study, the functional change of ciliated cells to mucus-secreting cells was examined with immunocytochemistry using anti-tubulin and anti-chondroitin 6-sulfate (C6S). Before hatching, most epidermal cells were labeled with anti-C6S in a granular fashion. Immunoelectron microscopy revealed that the anti-C6S-positive structure was the mucus granule. Ciliated epidermal cells lacked anti-C6S staining, but were strongly labeled with anti-tubulin. After hatching, most ciliated cells in the surface of the embryo disappeared. During their disappearance, some ciliated cells exhibited anti-C6S-positive granular labeling. This strongly suggests that the disappearance of ciliated cells is a functional conversion to mucus-secreting cells instead of shedding through cell death.

Actins↗