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PubMed1999

Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro.

BACKGROUND: We recently found evidence of tubular epithelial-myofibroblast transdifferentiation (TEMT) during the development of tubulointerstitial fibrosis in the rat remnant kidney. This study investigated the mechanisms that induce TEMT in vitro. METHODS: The normal rat kidney tubular epithelial cell line (NRK52E) was cultured for six days on plastic or collagen type I-coated plates in the presence or absence of recombinant transforming growth factor-beta1 (TGF-beta1). Transdifferentiation of tubular cells into myofibroblasts was assessed by electron microscopy and by expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin. RESULTS: NRK52E cells cultured on plastic or collagen-coated plates showed a classic cobblestone morphology. Culture in 1 ng/ml TGF-beta caused only very minor changes in morphology, but culture in 10 or 50 ng/ml TGF-beta1 caused profound changes. This involved hypertrophy, a loss of apical-basal polarity and microvilli, with cells becoming elongated and invasive, the formation of a new front-end back-end polarity, and the appearance of actin microfilaments and dense bodies. These morphological changes were accompanied by phenotypic changes. Double immunohistochemistry staining showed that the addition of TGF-beta1 to confluent cell cultures caused a loss of the epithelial marker E-cadherin and de novo expression of alpha-SMA. An intermediate stage in transdifferentiation could be seen with hypertrophic cells expressing both E-cadherin and alpha-SMA. De novo alpha-SMA expression was confirmed by Northern blotting, Western blotting, and flow cytometry. In particular, cells with a transformed morphology showed strong alpha-SMA immunostaining of characteristic microfilament structures along the cell axis. There was a dose-dependent increase in the percentage of cells expressing alpha-SMA with increasing concentrations of TGF-beta1, which was completely inhibited by the addition of a neutralizing anti-TGF-beta1 antibody. Compared with growth on plastic, cell culture on collagen-coated plates showed a threefold increase in the percentage of cells expressing alpha-SMA in response to TGF-beta1. CONCLUSION: TGF-beta1 is a key mediator that regulates, in a dose-dependent fashion, transdifferentiation of tubular epithelial cells into alpha-SMA+ myofibroblasts. This transdifferentiation is markedly enhanced by growth on collagen type I. These findings have identified a novel pathway that may contribute to renal fibrosis associated with overexpression of TGF-beta1 within the diseased kidney.

Actins↗
PubMed2002

Visualization by comprehensive microarray analysis of gene expression programs during transdifferentiation of mesophyll cells into xylem cells.

Plants have a unique transdifferentiation mechanism by which differentiated cells can initiate a new program of differentiation. We used a comprehensive analysis of gene expression in an in vitro zinnia (Zinnia elegans L.) culture model system to gather fundamental information about the gene regulation underlying the transdifferentiation of plant cells. In this model, photosynthetic mesophyll cells isolated from zinnia leaves transdifferentiate into xylem cells in a morphogenic process characterized by features such as secondary-wall formation and programmed cell death. More than 8,000 zinnia cDNA clones were isolated from an equalized cDNA library prepared from cultured cells transdifferentiating into xylem cells. Microarray analysis using these cDNAs revealed several types of unique gene regulation patterns, including: the transient expression of a set of genes during cell isolation, presumably induced by wounding; a rapid reduction in the expression of photosynthetic genes and the rapid induction of protein synthesis-associated genes during the first stage; the preferential induction of auxin-related genes during the subsequent stage; and the transient induction of genes closely associated with particular morphogenetic events, including cell-wall formation and degradation and programmed cell death during the final stage. This analysis also revealed a number of previously uncharacterized genes encoding proteins that function in signal transduction, such as protein kinases and transcription factors that are expressed in a stage-specific manner. These findings provide new clues to the molecular mechanisms of both plant transdifferentiation and wood formation.

Asteraceae↗
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↗
PubMed2002

Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis.

Though in the past believed to be a rare phenomenon, endothelial-mesenchymal transdifferentiation has been described with increasing frequency in recent years. It is believed to be important in embryonic vascular development, yet less is known regarding its role in the adult vasculature. Using FACS and immunomagnetic (Dynabeads) purification techniques (based on uptake of DiI-acetylated low-density lipoproteins and/or PECAM-1 expression) and double-label indirect immunostaining (for endothelial and smooth muscle [SM] markers), we demonstrate that mature bovine vascular endothelium contains cells of an endothelial phenotype (defined by VE-cadherin, von Willebrand factor, PECAM-1, and elevated uptake of acetylated low-density lipoproteins) that can undergo endothelial-mesenchymal transdifferentiation and further differentiate into SM cells (as defined by expression of alpha-SM-actin, SM22alpha, calponin, and SM-myosin). "Transitional" cells, coexpressing both endothelial markers and alpha-SM-actin, were consistently observed. The percentage of cells capable of endothelial-mesenchymal transdifferentiation within primary endothelial cultures was estimated as 0.01% to 0.03%. Acquisition of a SM phenotype occurred even in the absence of proliferation, in gamma-irradiated (30 Gy) and/or mitomycin C-treated primary cell cultures. Initiation of transdifferentiation correlated with disruption of cell-cell contacts (marked by loss of VE-cadherin expression) within endothelial monolayers, as well as with the action of transforming growth factor-beta(1). In conclusion, our in vitro data show that mature bovine systemic and pulmonary endothelium contains cells that can acquire a SM phenotype via a transdifferentiation process that is transforming growth factor-beta(1)- and cell-cell contact-dependent, but proliferation-independent.

Actins↗
PubMed2000

Transdifferentiation of esophageal smooth to skeletal muscle is myogenic bHLH factor-dependent.

Previously, coexpression of smooth and skeletal differentiation markers, but not myogenic regulatory factors (MRFs), was observed from E16.5 mouse fetuses in a small percentage of diaphragm level esophageal muscle cells, suggesting that MRFs are not involved in the process of initiation of developmentally programmed transdifferentiation in the esophagus. To investigate smooth-to-skeletal esophageal muscle transition, we analyzed Myf5nlacZ knock-in mice, MyoD-lacZ and myogenin-lacZ transgenic embryos with a panel of the antibodies reactive with myogenic regulatory factors (MRFs) and smooth and skeletal muscle markers. We observed that lacZ-expressing myogenic precursors were not detected in the esophagus before E15.5, arguing against the hypothesis that muscle precursor cells populate the esophagus at an earlier stage of development. Rather, the expression of the MRFs initiated in smooth muscle cells in the upper esophagus of E15.5 mouse embryos and was immediately followed by the expression of skeletal muscle markers. Moreover, transdifferentiation was markedly delayed or absent only in the absence of Myf5, suggesting that appropriate initiation and progression of smooth-to-skeletal muscle transdifferentiation is Myf5-dependent. Accordingly, the esophagus of Myf5(-/-):MyoD(-/-)embryos completely failed to undergo skeletal myogenesis and consisted entirely of smooth muscle. Lastly, extensive proliferation of muscularis precursor cells, without programmed cell death, occurred concomitantly with esophageal smooth-to-skeletal muscle transdifferentiation. Taken together, these results indicate that transdifferentiation is the fate of all smooth muscle cells in the upper esophagus and is normally initiated by Myf5.

Animals↗
PubMed2001

Formation of retinal pigment epithelium in vitro by transdifferentiation of neural retina cells.

Chick embryonic neural retina (NR) dedifferentiates in culture and can transdifferentiate spontaneously into retinal pigment epithelium (RPE). Both, primary RPE and transdifferentiated RPE (RPEt), are characterized by pigmentation, expression of RPE-specific protein, eRPEAG and lack of expression of the neural cell adhesion molecule, NCAM. In contrast, NR cells are unpigmented and express NCAM but not eRPE(AG). Functionally, both primary RPE and the RPEt cells display a pH(i) response to bFGF, which is different from that of the NR. We used these characteristics to distinguish cell types in primary cultures of chick NR and follow the changes in phenotype that occur during transdifferentiation. We show that the RPEt forms as small "islands" in the packed regions of the primary, "mother" NR cell sheets, in a stochastic process. Because of a small number of cells involved in the initiation of the transdifferentiation we refer to it as a "leader effect" to contrast it with the "community effect" which requires many competent cells to be present in a group to be able to respond to an inductive signal. The RPEt then expands centrifugally and underneath the surrounding NR sheet. To determine if the RPEt maintains its identity in isolation while displaying the RPE-typical phenotypic plasticity, we explanted the islands of RPEt and treated half of them with bFGF. The untreated RPEt maintained its closely packed, polygonal pigmented phenotype but the bFGF-treated RPEt transdifferentiated into a non-pigmented, NR-like phenotype, indicating that RPEt encompasses the full differentiation repertoire of native RPE.

Animals↗
PubMed2002

[Aristolochic acid induced transdifferentiation and apoptosis in human tubular epithelial cells in vitro].

OBJECTIVE: To examine the possible role of aristolochic acid (AA) in transdifferentiation and apoptisis of human tubular epithelial cell line (HKC). METHODS: Cultured HKC cells were divided into five groups: serum-free (negative control) and treatment with AA at the concentrations of 5 mg/L, 10 mg/L, 20 mg/L and 40 mg/L for 48 hours, respectively. Transdifferentiation of HKC cells was observed with the following methods: detection of the expression of vimentin and cytokeratin of HKC cells with indirect immunoflourescence, determination of expression of E-cadherin and alpha-smooth muscle actin (alpha-SMA) by indirect immunohistochemical double staining, and determination of the proportion of alpha-SMA (+) HKC cells by flow cytometry. The apoptosis of HKC cells was observed with Giemsa staining, TUNEL reaction and agarose gel electrophoresis, and the ratio of apoptotic HKC cells was quantitatively analyzed by flow cytometry with propidium iodide staining. RESULTS: The expression of cytokeratin and E-cadherin reduced and that of vimentin increased in HKC cells treated with 10 mg/L of AA for 48 hours, and the expression of alpha-SMA (+) in HKC cells treated with 10 mg/L of AA (14.17 +/- 0.61)% was significantly higher than that in serum-free controls (3.57 +/- 0.52)%. Apoptosis of HKC cell treated with 40 mg/L of AA for 48 hours was 53.4%, significantly higher than that in serum-free controls (2%). Treatment with 5 mg/L of AA and 20 mg/L of AA could not induce apoptosis and transdifferentiation of cells. CONCLUSIONS: Treatment with relatively low concentration of AA (10 mg/L) might induce slight transdifferentiation in cultured HKC cells and that with higher concentration of AA (40 mg/L) for 48 hours might induce apparent apoptosis of these cells, which suggested that transdifferentiation and apoptosis of tubular epithelial cells probably played important roles in aristolochic acid-induced nephropathy.

Actins↗
PubMed2002

[Transdifferentiating of adult human pancreatic stem cells into islet cells].

OBJECTIVE: To understand and improve the transdifferentiation of pancreatic stem cells into islet cells through isolation, cultivation and transdifferentiation of adult human pancreatic duct cells. METHODS: A portion of adult human pancreas was digested with collagenase, followed by incontinuous density gradient to separate islets from the acinar and ductal tissue. Duct epithelial cells were cultivated in CMRL1066 and then in serum-free DMEM/F12 medium with the addition of growth factors for 27 days. Samples were taken at different time points for light and electron microscopic examination and for immunocytochemical study with antibodies against transdifferentiation gene PDX-1 and protein CK-19. Amylase and insulin contents in the medium were assayed. RESULTS: A large number of duct epithelial cells were harvested after the isolation of islets. Some duct epithelial cells were PDX-1 and CK-19 positive at day one and duct epithelial cells proliferated and expanded rapidly and then transdifferentiated into stem cells and finally 3D islets. 760 islets were harvested from each gram of pancreatic tissue on day 27. CONCLUSIONS: Adult pancreatic duct cells are potential stem cells and could be transdifferentiated into islet cells in vitro under appropriate conditions.

Adult↗
PubMed1987

Inhibition of conjunctival transdifferentiation by topical retinoids.

During the healing of a total corneal epithelial defect extending beyond the limbus, conjunctival transdifferentiation can be inhibited by corneal vascularization as evidenced by the lack of morphological transformation of the conjunctival epithelium into a cornea-like epithelium and the persistence of goblet cells on the corneal surface. We speculated that corneal vascularization might play a causative role in inhibiting conjunctival transdifferentiation, and examined the hypothesis that vitamin A or retinoids might be one of the blood-borne factors in modulating this process. To test this hypothesis, we created total corneal epithelial defects extending 3 mm beyond the limbus in rabbits using n-heptanol, and segregated the resultant corneas into nonvascularized and vascularized groups. After re-epithelialization, both groups received topical 0.1% Etretinate (Roche-Hoffmann, Nutley, NJ) or 13-cis retinoic acid in corn oil three times a day for 8 weeks. Controls received corn oil only. The extent of transdifferentiation was analyzed by assaying goblet cell density and distribution using flat-mount preparations and Alcian blue and periodic acid-Schiff stains (Fischer Scientific Co., Fair Lawn, NJ) and by conventional histology. Topical retinoid application inhibited conjunctival transdifferentiation in nonvascularized corneas to the same extent as that caused by corneal vascularization, suggesting that vitamin A is an important blood-borne factor for goblet cell maintenance. Its relative deficiency in the normal avascular cornea may explain why conjunctival transdifferentiation occurs.

Administration, Topical↗
PubMed1984

Goblet cell density and vascularization during conjunctival transdifferentiation.

After debridement of the entire corneal epithelium with n-heptanol, two groups of rabbit corneas were segregated according to the extent of corneal neovascularization. Using a new topographic goblet-cell counting method and routine histology, the authors have reexamined the process of conjunctival transdifferentiation and compared the changes of goblet-cell density and morphology between nonvascularized and vascularized groups for a follow-up period of 167 days. Analysis of the total goblet-cell density disclosed that no goblet cells appeared on the corneal surface during the entire period of reepithelialization. After that, two phases were identified with respect to goblet-cell density: phase I (day 0-17) and phase II (after day 17). In phase I, both groups had a similar surge of goblet cells, with the peak occurring between days 7 and 11, suggesting little correlation with vascularization. Morphologic studies indicated the presence of a prominent centripetal cellular migration. In phase II, the nonvascularized group showed a rapid decline in goblet-cell density, and as a result the morphologic transdifferentiation into a cornea-like epithelium was completed on day 43. The changes of goblet cells to a smaller size and the presence of a more acidic mucin in the centrifugal receding zone, suggested that transdifferentiation on nonvascularized corneas is a process involving changes of cellular differentiation. In contrast, the vascularized group maintained a high plateau of goblet-cell density and an epithelium with conjunctival characteristics until day 167. This result disclosed that retardation of conjunctival transdifferentiation by corneal vascularization was in phase II. The possible role of vascularization in the modulation of conjunctival transdifferentiation is discussed.

Animals↗
PubMedDate not supplied

[Mechanisms of transdifferentiation and their relation to induction and competence].

The ways of transdifferentiation are considered: spontaneous and induced. Spontaneous transdifferentiation taking place after the disaggregation of cells in the clonal and cell cultures is determined by the competence of the transforming cells themselves. Induced transdifferentiation is determined not only by the competence but also by the effect of external inducing factors. It is suggested that the direction of induced transdifferentiation depends on the ratio between the external and internal inducing factors and on the character of cell cycles. It is probable that the inducing factors entering the cells during the early embryonic induction are reproduced in the cells in a dormant state and some of them do not reveal their presence until appropriate conditions are set. When the cells are isolated in the cultures, the ratio of these factors inside the cell changes and a competence to transdifferentiation is revealed which arises as early as during induction.

Animals↗
PubMed2000

Intimal thickening involves transdifferentiation of embryonic endothelial cells.

Morphological studies have hypothesized different origins for the precursors of the vascular smooth muscle cells (SMCs). The intriguing possibility that intimal SMCs may arise from the endothelium has newly emerged. As a first step towards understanding of the possible mechanisms involved in the transdifferentiation of endothelium into smooth muscle cells, we characterized the in vivo phenotype of the cells located in the aortic wall (distal to the aortic arches). This was accomplished using advanced stages of chicken embryo development. Furthermore, we investigated whether the cells present at the intimal thickening derive from the endothelial cell transdifferentiation. Immunolabeling of serial cryosections suggested that mesenchymal cells observed in the intimal thickening may arise from the endothelium. These cells may persist either as non-muscle throughout the development or possibly convert to cells expressing smooth muscle alpha-actin (SM alpha-actin). To determine whether endothelial cells may actually transdifferentiate into mesenchymal cells, aortic explants from 14-day-old chicken embryos (stage 40) were used. We found that explanted endothelial cells lose their cobblestone-appearance and migrate toward cell-free area. Some of these cells maintain the vWf immunoreactivity, whereas other cells coordinately lose vWf and gain SM alpha-actin expression (transitional cells). Taken together these findings strongly support the possibility that embryonic aortic endothelial transdifferentiate into mesenchymal cells, some of which express SM alpha-actin. Since TGFbeta-3 is considered an essential factor during epithelial to mesenchymal transitions in earlier chicken heart development, we also investigated the distribution of this growth factor at day 14. Our observations indicated that the immunoreactivity for TGFbeta-3 in this stage may be associated with migrating mesenchymal cells and that this immunoreactivity appears to decrease as cell differentiation advances. Therefore, the present study provides evidence that could help to explain 1) the presence of cells displaying a phenotype reminiscent of fetal-like cells in the normal chicken aorta and in the intimal region of the human aorta; 2) the SM lineage diversity in the chicken embryo reported by others; 3) a subpopulation of immature cells in the subendothelial region of the main pulmonary arteries of fetal, neonatal and adult bovines; and 4) the presence of intimal cushions, intimal pads, eccentric and diffuse intimal thickening that are observed in mammalian and avian vessels at birth.

Actins↗
PubMed1998

Spontaneous transdifferentiation of quail pigmented epithelial cell is accompanied by a mutation in the Mitf gene.

An ectopic neural retina is formed at the outer layer of the retina in the silver homozygote (B/B) of the Japanese quail. In situ hybridization and immunohistochemical analysis revealed that cells in the outer layer of retina first expressed a pigment-cell-specific gene, mmp115, and then began to express a neural marker in B/B embryos, indicating that the ectopic neural retina is formed via transdifferentiation of differentiated pigmented epithelial cells (PECs). An in vitro study revealed that cultured retinal PECs (rPECs) from B/B embryos exhibit less pigment granule and a higher growth rate than cells from heterozygotes (B/+). B/+ PECs stopped proliferating when confluency was reached, while B/B PECs continued to proliferate. Some B/B cells overlaid other B/B cells and formed lentoid bodies. Immunological analysis revealed that B/B rPECs transdifferentiated to lens cells and neural cells in vitro with no addition of basic FGF (bFGF), while B/+ rPECs required bFGF to transdifferentiate. Expression of PEC-specific genes, mmp115, tyrosinase, and TRP-1, was downregulated, but that of Mitf and pax6 was upregulated in B/B PECs. Antibody against Mitf stained the nucleus of B/+ PECs but not that of B/B cells, suggesting that the normal Mitf is not present in the silver homozygote due to mutation. Sequence analysis revealed that Mitf from the silver homozygote has an amino acid substitution in the basic region and is truncated in the C-terminal region. Transient transfection analysis revealed that Mitf from the silver homozygote exhibits a lower level of activity than wild-type Mitf with respect to transactivation of the mmp115 promoter. Furthermore, overexpression of chicken Mitf induced normal pigmentation in B/B rPECs. These results strongly suggest that the silver phenotype is caused by the mutation of Mitf and that Mitf plays a critical role in rPEC differentiation and transdifferentiation.

Amino Acid Sequence↗
PubMed1995

Adrenal chromaffin cells transdifferentiate in response to basic fibroblast growth factor and show directed outgrowth to a nerve growth factor source in vivo.

Chromaffin cells exposed to basic fibroblast growth factor (bFGF) in vitro express characteristics of sympathetic neurons, extend neurites, and become dependent on nerve growth factor (NGF) for survival. We explored whether the growth factor responsiveness of chromaffin cells could be exploited to enhance the transdifferentiation, neurite outgrowth and functional efficacy of chromaffin cells implanted into rats with unilateral 6-hydroxydopamine lesions. Cografts of neonatal chromaffin cells and fibroblasts genetically modified to produce bFGF were placed into the dopamine-depleted striatum of adult rats. Either control-transfected or NGF-producing fibroblasts were then transplanted 1 mm distal to the cograft. Chromaffin cells transdifferentiated under the influence of bFGF, as indicated by the growth of neurites and the expression of neuron-specific proteins. Distal grafts of NGF-producing fibroblasts successfully induced chromaffin neurites to traverse through the host parenchyma to the NGF source. In the absence of NGF fibroblast grafts, neither neurite extension nor good, long-term survival of the chromaffin-derived neurons was observed. Assessments of apomorphine-induced rotational behavior 2- and 4-weeks postgrafting revealed no behavior improvements in any of the groups. These results indicate that localized sources of growth factors are effective in inducing the transdifferentiation of grafted chromaffin cells as well as the extension of chromaffin-derived neurites into the host parenchyma. Such chromaffin cell-derived neurons are, however, functionally ineffective in this rat model of Parkinson's disease. Whether the lack of behavioral improvement reflected the tropic growth of neurites to an inappropriate striatal region or the noradrenergic nature of the chromaffin cell-derived neurons remains to be clarified. Nonetheless, these results caution that promoting transdifferentiation and neurite extension from engrafted chromaffin cells may not be sufficient to achieve desired functional effects of such grafts.

Adrenal Medulla↗
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↗
PubMed1987

Glucose metabolism in transdifferentiating and glucose-blocked cultures of chick embryo neuroretinal cells: an inverse relationship between glycogen and delta-crystallin accumulation.

Chick embryo neuroretinal (NR) cells transdifferentiate extensively into lens when cultured for several weeks in low-glucose (FH) medium, but fail to do so when high levels of supplementary glucose (FHG) are present. We show here that most aspects of glucose metabolism are promoted in high-glucose cultures, including lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G-6-PDH) activities, 2-deoxyglucose uptake, pentose shunt activity and lactate production. Continuous supplementation of high-glucose cultures with low levels of ouabain (FHGO) significantly lowers 2-deoxyglucose uptake, from FHG levels down towards FH levels, especially during the early stages of NR culture. Much later, extensive transdifferentiation into lentoids (with concomitant delta-crystallin accumulation) occurs in these FHGO cultures, which thus resemble FH rather than FHG controls. Another parameter strongly affected by ambient glucose levels is the accumulation of glycogen. Both glycogen itself and glycogen synthetase activity increase steadily in FHG cultures, but decrease slightly under FH conditions. Glycogen accumulation in FHG cultures is largely confined to glial-like cells, particularly those underlying clusters of neurones. Other studies have shown that glial differentiation in vitro is promoted by histotypic interactions with retinal neurones. Thus high glucose may act in concert with neuronal influences to stimulate or stabilize the normal differentiation of retinal glial cells, whose characteristic features in vivo include glycogen synthesis and storage. Furthermore, we show that supplementation of high-glucose cultures with forskolin or dibutyryl cyclic AMP (both of which promote glycogenolysis) results in a slower rate of glycogen accumulation and in enhanced transdifferentiation into lens. In both respects, the forskolin- and dibutyryl cAMP-supplemented FHG cultures are intermediate between FH and FHG controls. Thus the enhancement of normal glial differentiation in NR cultures by high glucose may inhibit or preclude subsequent transdifferentiation into lens.

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↗
PubMed1993

Transdifferentiation.

Recent progress in studies of development and differentiation has greatly stimulated analysis of transdifferentiation, and more cell types capable of transdifferentiation have been documented. Growth factors must be essential, key factors in the regulation of the transdifferentiation process, in cooperation with components of the extracellular matrix, which helps to stabilize the differentiated state of tissues. Trials to induce transdifferentiation artificially by transfection of genes have also begun.

Animals↗