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PubMed2005

Schwann cells induce neuronal differentiation of bone marrow stromal cells.

Bone marrow stromal cells are multipotent stem cells that have the potential to differentiate into bone, cartilage, fat and muscle. Recently, bone marrow stromal cells have been shown to have the capacity to differentiate into neurons under specific experimental conditions, using chemical factors. We now describe how bone marrow stromal cells can be induced to differentiate into neuron-like cells when they are co-cultured with Schwann cells. When compared with chemical differentiation, expression of neuronal differentiation markers begins later, but one week after beginning co-culture, most bone marrow stromal cells showed a typical neuronal morphology. Our present findings support the transdifferentiation of bone marrow stromal cells, and the potential utility of these cells for the treatment of degenerative and acquired disorders of the nervous system.

Animals↗

PubMed2003

Neonatal lupus syndromes.

The neonatal lupus syndromes, although quite rare, provide an excellent opportunity to examine disease from bench to bedside. During the past year numerous publications have reported basic and clinical research. Although anti-SSA/Ro-SSB/La antibodies are detected in more than 85% of mothers whose fetuses are identified with conduction abnormalities in a structurally normal heart, when clinicians applied this testing to their pregnant patients, the risk for a woman with the candidate antibodies to have a child with congenital heart block was at or below one in 50. Although the precise pathogenic mechanism of antibody-mediated injury remains unknown, it is clear that the antibodies alone are insufficient to cause disease, and fetal factors are likely contributory. In vivo and in vitro evidence supports a pathologic cascade involving apoptosis of cardiocytes, surface translocation of Ro and La antigens, binding of maternal autoantibodies, secretion of profibrosing factors from the scavenging macrophages, and transdifferentiation of cardiac fibroblasts to a myofibroblast scarring phenotype. Cross-reactivity of anti-52-kD SSA/Ro antibodies with a serotoninergic cardiac receptor, 5-hydroxytryptamine (HT)4, has been suggested but remains unconfirmed. The spectrum of cardiac abnormalities continues to grow, with varying degrees of block identified in utero and reports of late-onset cardiomyopathy (some of which display endocardial fibroelastosis). Moreover, there is now clear documentation that incomplete blocks (including those improving in utero with dexamethasone) can progress postnatally, despite the clearance of the maternal antibodies from the neonatal circulation. Better echocardiographic measurements that identify first-degree block in utero may be the optimal means of approaching pregnant women at risk. Prophylactic therapies, including treatment with intravenous immunoglobulin, await larger trials. Reassuringly, most children with neonatal lupus syndromes do not develop rheumatic diseases, although follow-up is limited to late adolescence. To further efforts both at the bench and bedside, national research registries established in the United States and Canada are critical.

Adult↗

PubMedDate not supplied

Cardiac cell therapy: a treatment option for cardiomyopathy.

Cardiomyopathy is a common clinical disorder affecting the heart muscle. This disease process frequently leads to congestive heart failure and will often progress to end-stage heart failure. Present standard of care treatment options for cardiomyopathy include medical management, lifestyle changes, and surgical procedures including left ventricular assist devices as a destiny therapy or bridging to heart transplantation. Even despite advances in drug therapy, mechanical assist devices, and organ transplantation, more than half of the persons with cardiomyopathy will die within 5 years of diagnosis. Small uncontrolled clinical trials have demonstrated cardiac stem cells as a treatment option for cardiomyopathy. The theory for the individual or combined mechanism of action for stem cells includes (1) transdifferentiation to blood vessels or myocardium, (2) fusion with the native dysfunctional myocytes to augment function, and (3) homing that may be a systemic or panacrine response for recruiting other cells, and growth factors to help improve oxygen delivery and myocardial function. The field of cardiac cell therapy is rapidly progressing to gather more data with intermediate-size, double-blinded trials that will demonstrate the safety and efficacy of cell therapy.

Cardiomyopathies↗

PubMed2000

Differentiation of islet cells in long-term culture.

Our previous studies in the hamster pancreatic cancer model have shown that exocrine pancreatic cancer arises from ductal/ductular cells, as well as from within the islets, most probably from islet precursor (stem) cells. To identify and characterize these cells, we established a long-term culture from isolated hamster islets and investigated their growth, differentiation, and expression of biomarkers. Islets maintained their original form and structure within the first 14 days in culture. However, beginning at day 7, ductular structures began to form within the islets. At day 21 in culture, acinar cells, intermediary cells, oncocytes, and cells comparable to pancreatic hepatocytes also appeared between ductular and endocrine cells. The number of duct-like cells gradually increased, whereas the number of hormone-producing cells decreased. After 35 days in culture, the exocrine cells disappeared, and undifferentiated cells formed a monolayer. These cells expressed cytokeratins, alpha1-antitrypsin, transforming growth factor-alpha, epidermal growth factor receptor, carbonic anhydrase II, vimentin, laminin, and showed binding to tomato lectin and Phaseolus vulgaris leukoagglutinin. They did not express the regulatory transcriptional factors, insulin-promoting factor 1, NKx6.1, Pax6, and NeuroD. The results thus indicate that islet cells have potential to form exocrine cells. At present, it is not clear whether these cells originate from preexisting stem cells or from transdifferentiated islet cells.

Animals↗

PubMed1998

Macular function testing in a German pedigree with North Carolina macular dystrophy.

BACKGROUND: Our purpose was to investigate central visual function in North Carolina macular dystrophy (MCDR1). A German family with genetically proven MCDR1 was followed for more than 20 years. METHODS: In addition to routine clinical examinations, static and kinetic fundus perimetry was performed with the scanning laser ophthalmoscope. The center of fixation was determined. RESULTS: Visual acuity was 0.6 or better in all but one eye of seven members of this family and did not markedly change during follow-up. Fundus examination confirmed that the fixation was at the nasal edge of the central scar in five affected eyes with reduced stability of fixation. One eye had a prominent gliotic membrane, and fixation was within this area. CONCLUSIONS: Patients had nearly normal visual acuity even though they presented with deep central scotomas and a shift of the center of fixation away from the fovea. Because MCDR1 has good long-term functional prognosis, there might be an early transdifferentiation of the new locus of fixation.

Adolescent↗

PubMedDate not supplied

Expression of connective tissue growth factor and its potential role in choroidal neovascularization.

BACKGROUND: To determine the expression of connective tissue growth factor (CTGF) in choroidal neovascularization. METHODS: Surgically excised choroidal neovascular membranes (CNVMs) were obtained at vitrectomy from eight eyes with age-related macular degeneration, five eyes with high myopia, and two eyes with angioid streaks. Light microscopic immunohistochemical analysis was performed to detect CTGF, transforming growth factor beta 1 (TGF-beta1), vascular endothelial growth factor (VEGF), pancytokeratin, and smooth muscle actin (SMA). RESULTS: CNVMs were classified by fibrotic status as cellular CNVM, moderate fibrous CNVM, and extensive fibrous CNVM. CTGF expression was found in vascular cells, stromal cells, and retinal pigment epithelium (RPE) cells. For the stromal cells, fibroblastlike cells were most strongly positive for CTGF. CTGF immunoreactivity in the stroma was stronger in the fibrous CNVMs than in the cellular CNVMs. Immunohistochemical analysis of serial sections revealed colocalization of CTGF with TGF-beta1 and VEGF; colocalization of CTGF with pancytokeratin and SMA was also found. CONCLUSION: Our findings suggest that transdifferentiated RPE cells and vascular cells possess remarkable CTGF expression in CNVMs. This expression of CTGF may stimulate fibroblasts to produce extracellular matrix and may promote angiogenesis in vascular cells. Colocalized TGF-beta1 and VEGF may also contribute the upregulation of CTGF.

Aged↗

PubMed2005

Adult stem cell therapy in stroke.

PURPOSE OF REVIEW: Acute cerebral infarction causes irreversible locally restricted loss of the neuronal circuitry and supporting glial cells with consecutive functional deficits and disabilities. The currently available and effective therapy targets fast vessel recanalization accompanied by symptomatic measures. Research activities focusing on stem cells, which represent a promising source for organotypic cell replacement and functional recovery after stroke, have gained momentum in recent years, making regenerative cell-based therapies a much more feasible realistic approach. This review provides an update about preclinical and clinical cell-based studies in stroke focusing on stem cells derived from the adult central nervous and hematopoetic systems. RECENT FINDINGS: Endogenous neural stem cells, which have been shown to reside throughout life in the central nervous system, have the capacity to replace lost neurons in models for numerous disorders, including cerebral ischemia. Considering adult neural stem cell transplantation as a regenerative strategy after stroke, progress has been made in isolating human adult neural stem cells and demonstrating the feasibility of autologous neural stem cell transplantation. An increasing number of studies provide evidence that hematopoietic stem cells, either after stimulation of endogenous stem cell pools or after exogenous hematopoietic stem cell application (transplantation), improve functional outcome after ischemic brain lesions. Various underlying mechanisms such as transdifferentiation into neural lineages, neuroprotection through trophic support, and cell fusion have been deciphered. SUMMARY: Many preclinical studies employing adult stem cell-based strategies hold great promise. For endogenous approaches the correlate of cell replacement underlying functional improvement needs to be demonstrated. Transplantation approaches on the experimental level need further development before clinical application can be considered.

Adult↗

PubMed2001

Renal fibrosis: an update.

Tubulointerstitial fibrosis invariably accompanies the course of chronic renal failure towards end-stage renal disease. Tubular epithelial cells, the predominant cell type in the tubulointerstitium, are increasingly being recognized for playing a dominant role as mediators of renal fibrogenesis. Tubular epithelial cells become activated either by the glomerular ultrafiltrate from their apical side or by mononuclear cells from their basolateral side. They initiate the scarring process by secreting chemokines, which in return attract mononuclear cells as well as growth factors that stimulate interstitial fibroblasts. In later phases of renal fibrogenesis, cellular changes of tubular epithelial cells contribute to the chronic impairment of renal function. Whereas tubular epithelial cells react by proliferation or hypertrophy to initial stimuli, they may undergo apoptosis or transdifferentiate into fibroblasts, and thus contribute to tubular atrophy in later stages of progressive renal disease. Resident interstitial fibroblasts are also important in renal fibrogenesis, and recent research has demonstrated that these cells are much more heterogeneous than expected. Cytokines such as fibroblast growth factor type 2 and epithelial growth factor have been shown to be pro-fibrogenic, whereas hepatocyte growth factor and bone morphogenic protein type 7 may inhibit fibrogenesis. Despite recent progress, further research is mandatory for a better understanding and the development of novel therapeutic approaches.

Fibrosis↗

PubMed2004

The role of angiotensin II in kidney embryogenesis and kidney abnormalities.

PURPOSE OF REVIEW: The renin-angiotensin system has a major role in the control of blood pressure and homeostasis balance. It also plays a fundamental role in kidney development. Recent insights into how the angiotensin-generating cascade controls developmental processes and homeostasis, and, when defective, causes disease, are discussed. RECENT FINDINGS: The role of the renin-angiotensin system in kidney development is now widely accepted. New findings discussed in this review include the discovery of the capacity of the kidney to produce its own blood cells simultaneously with in-situ blood vessel formation, a process referred to as hemo-vasculogenesis. In addition, the role of the renin-angiotensin system in hematopoiesis is reviewed. Also discussed are the effects of angiotensin on branching morphogenesis and the development of hypertension in the adult as a result of a reduction in nephron number during nephrogenesis. Furthermore, the relationship between angiotensin and transdifferentiation of epithelial cells into fibroblasts is described. SUMMARY: The aforementioned advances help to clarify pathological processes such as extramedullary hematopoiesis, post-transplant erythrocytosis, the relationship between nephron number and hypertension, and the role of angiotensin and other growth factors in renal fibrosis. The molecules and pathways whereby angiotensin contributes to the processes mentioned above are beginning to be elucidated.

Angiotensin II↗

PubMed2000

Current status of limbal conjunctival autograft.

The past decade has witnessed several major advances in the field of ocular surface reconstruction. It is now established that the limbal and corneal epithelia belong to the same clonogenic lineage and that conjunctival transdifferentiation does not occur. These facts have engendered the increasing use of limbal transplantation in several ocular conditions involving limbal compromise. Many reports on this procedure have been published in the past year. They add to the growing body of evidence that limbal transplantation is efficacious in replenishing the stem cell pool, promoting improved vision and enhancing ocular comfort. Recent clinical studies on limbal autograft transplantation also underscore the importance of preoperative impression cytology in donor eyes, highlight the fact that transplantation in inflamed eyes is to be avoided, and indicate that the procedure is likely to provide better outcomes if performed several months after ocular surface burns. The appreciation of the utility of amniotic membrane transplantation in ocular surface reconstruction has provided a surgical tool to use in tandem with limbal transplantation. Questions such as why limbal autografts fail, the long-term results of LAT, and whether limbal inclusion is mandatory during conjunctival transplantation after pterygium excision have not been answered fully. Studies on long-term outcomes with limbal allograft transplantation and those reporting on experience with newer techniques such as epithelial transplantation using tissue culture-cultivated epithelium are likely to provide better perspectives on the best way to reconstruct the ocular surface in stem cell-deficient eyes.

Cell Transplantation↗

PubMed2003

Stem-cell "plasticity": befuddled by the muddle.

In the past 4 years, multiple reports have suggested that stem cells derived from adult tissues can differentiate outside their tissue of origin, challenging long-accepted tenets of developmental biology. This concept of stem-cell "plasticity" has helped to galvanize research on stem cells due to the myriad therapeutic possibilities. However, there are wide discrepancies in the reported frequencies of so-called transdifferentiation events, from recent reports of negative data to reports of the contribution in some tissues and systems reaching as much as 20%. The evidence for and against stem-cell plasticity is reviewed here as well as some of the possible sources of the experimental variation.

Animals↗

PubMed2005

Adipogenic phenotype of hepatic stellate cells.

Transdifferentiation of hepatic stellate cells (HSC) constitutes a major cellular event in the genesis of alcoholic liver fibrosis and cirrhosis and molecular mechanisms underlying this process is incompletely understood. Our laboratory proposed several years ago that HSC quiescence requires the transcriptional program known to be integral to preadipocyte to adipocyte differentiation. In support of the hypothesis, our research demonstrates the expression of adipogenic transcription factors (C/EBPs, PPARgamma, SREBP-1c, LXRalpha) and adipocyte-specific genes (adipsin, resistin) are high in quiescent HSC and depleted in activated HSC. Three gain-of-function approaches have been taken to test this notion: the treatment of activated HSC with the adipocyte differentiation cocktail; ectopic expression of PPARgamma or SREBP-1c. All three treatments coordinately upregulate a panel of putative adipogenic transcription factors and cause morphologic and biochemical reversal of activated HSC to quiescent cells. These findings establish a new conceptual framework for the treatment of liver fibrosis and propose an intriguing notion concerning the plasticity of HSC.

Adipogenesis↗

PubMed2005

Anti-TGF-beta strategies for the treatment of chronic liver disease.

Permanent alcohol abuse may lead to chronic liver injury with deleterious sequelae such as liver cirrhosis and hepatocellular carcinoma. Mechanisms of fibrogenesis encompass recruitment of inflammatory cells at the site of injury and cytokine mediated activation of hepatic stellate cells (HSC) with accumulation of interstitial collagens. HSC transdifferentiation and accompanying apoptosis result in destruction of liver architecture and are therefore key steps of disease progression. TGF-beta represents the main profibrogenic cytokine in liver fibrosis and other fibroproliferative disorders by inducing extracellular matrix deposition as part of the wound healing response. In parallel, TGF-beta triggers hepatocytes that are strongly responsive for this cytokine, to undergo apoptosis, thereby providing space for HSC proliferation and generation of a collagenous matrix. Anti TGF-beta approaches were established and successfully utilized for the treatment of experimental fibrogenesis. Dominant negative TGF-beta receptors (TbetaR), generated by fusing the Fc domain of human IgG and the N-terminal (extracellular) fragment of TbetaRII (Fc:TbetaRII) were applied to suppress fibrosis. Similarly TGF-beta binding proteins like decorin, antagonistic cytokines such as bone morphogenetic protein-7, hepatocyte growth factor, IL-10, or IFN-gamma were as efficient as camostat mesilate, a protease inhibitor that possibly abrogated proteolytic activation of TGF-beta. Further, our group recently overexpressed Smad7 in bile duct ligation induced liver fibrosis and achieved efficient inhibition of intracellular TGF-beta signaling, thereby counteracting profibrogenic effects in cultured HSC and in vivo. A direct link between the effect of alcohol and TGF-beta exists through reactive oxygen species that are generated in liver cells by alcohol metabolism and represent activators of TGF-beta signaling. Thus, soluble TbetaRII expression reduced experimental fibrogenesis in vitro and in vivo partially by decreasing intracellular ROS and inhibiting NADH oxidase. Approaches that specifically target profibrogenic TGF-beta signaling are promising to treat alcoholic liver disease in the future. However, to ensure safety for the patients to be treated, approaches with strong specificity need to be established. Therefore, it is essential to delineate the profibrogenic actions of TGF-beta and the influence of alcohol abuse in molecular detail.

Animals↗

PubMed2004

Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis.

PURPOSE OF REVIEW: There is an intense interest in the potential of circulating blood cells and epithelium-related nonfibroblast cells to change into matrix synthesizing fibroblasts and myofibroblasts. These sources of fibroblasts may have importance in systemic sclerosis (scleroderma). RECENT FINDINGS: Epithelial cells from different sources can transition into fibroblasts and myofibroblasts in response to transforming growth factor beta and other growth factors/cytokines. This is called epithelial-mesenchymal transition (EMT). EMT has been repeatedly demonstrated to occur in several models of renal fibrosis including lupus prone mice. Quite unexpectedly, bone morphogenic protein 7 prevents EMT and protects lupus mice and other renal fibrosis models from developing fibrosis in the kidneys. Human peripheral blood mononuclear cells under different conditions of culture give rise to several different types of fibroblast-like cells. In SSc, it has been observed that the sera have low levels of serum amyloid protein. Serum amyloid protein has been found to inhibit the generation of fibrocytes from CD14 precursors. The implications of these potential sources of fibroblasts and myofibroblasts in systemic sclerosis and related rheumatic diseases are discussed. SUMMARY: Fibroblasts and myofibroblasts in skin and internal organs of patients with systemic sclerosis and related diseases may possibly arise not only from the resident fibroblast population but from epithelial cells, pericytes, monocytes, and other progenitors from the circulating pool of hematopoietic cells and stem cells. These alternative sources of fibroblasts would best be treated by specifically targeting the transition or transdifferentiation process by which cells change into fibroblasts.

Fibroblasts↗

PubMed2006

Progressive replacement of oral mucosa by conjunctiva in osteo-odonto-keratoprosthesis: preliminary observations.

PURPOSE: In a Strampelli osteo-odonto-keratoprosthesis, a patch of oral mucosa is frequently used to cover the ocular surface after implantation of an osteodental lamina into the eye. In many cases, gross modifications in the eye covering become apparent a few years later. The aim of this study was to investigate the histologic findings in the clinically modified ocular surface. METHOD: Biopsies were performed in 7 patients at the junction between the osteodental acrylic lamina and surrounding modified oral mucosa, during surgery for local plastic reconstruction or positioning of antiglaucoma silicone tubes. Specimens were examined by light microscopy. RESULTS: Six of the 7 clinically modified specimens corresponded microscopically to conjunctiva. Typical oral mucosa could still be observed overlying the osteodental acrylic lamina. CONCLUSIONS: The production of local regulatory factors is a possible explanation for the survival of oral mucosa over the osteodental acrylic lamina, whereas their absence in distant areas may have induced the oral mucosa to transdifferentiate into a conjunctival-type lining. Alternatively, conjunctival regrowth from forniceal stem cells should be taken into consideration.

Acrylates↗

PubMed2002

Association of spasmolytic polypeptide-expressing metaplasia with carcinogen administration and oxyntic atrophy in rats.

Spasmolytic polypeptide (TFF2)-expressing metaplasia (SPEM) is a gastric metaplastic lineage associated with the development of intestinal-type gastric adenocarcinoma. To study the etiology of this potential neoplastic precursor metaplasia, we used surgical rat models of remnant gastric adenocarcinoma studied with and without exposure to nitroso carcinogen. Animals with truncal vagotomy without duodenogastric reflux procedures demonstrated normal mucous neck cell spasmolytic polypeptide (SP) immunostaining. In these animals, anti-proliferating cell nuclear antigen (PCNA)-labeled nuclei were found in the normal midgland progenitor zone. Rats that received anatomic alterations that augmented the degree of duodenogastric reflux, however, revealed expansion of basally placed SP immunoreactive cells with early phenotypic changes of SPEM. Seventy percent of animals with antrectomy and carcinogen (with or without vagotomy) developed SPEM at the base of the gastric mucosa. In association with the appearance of this metaplastic lineage, a distinct second zone of PCNA-labeled nuclei developed in the deepest portion of the mucosa. Of interest, three animals demonstrating these changes developed intestinal-type gastric adenocarcinoma. Finally, we studied the immunostaining pattern of intrinsic factor, normally a chief cell marker in rat fundic mucosa. In animals with SPEM, we observed coexpression of SP and intrinsic factor in SPEM cells at the base of the mucosa. These findings support our hypothesis that SPEM develops from a second progenitor cell population, reflecting either the unmasking of a cryptic zone or transdifferentiation of chief cells.

Animals↗

PubMed2006

Mesenchymal stromal cells.

PURPOSE OF REVIEW: Our understanding of the biology and properties of mesenchymal stem cells or multipotent mesenchymal stromal cells has expanded dramatically over the last 3 years and is likely to have an impact on clinical practice in the near future, making a review of this topic both timely and relevant RECENT FINDINGS: Recommendations regarding nomenclature and the definition of mesenchymal stromal cells have been proposed, a rapidly dividing population within the mesenchymal stromal cell compartment has been better defined and the ability of these cells to exhibit characteristics of cells from a variety of lineages has been extended. The notion that tissue repair with mesenchymal stromal cells is related to transdifferentiation has been re-evaluated and, for the myocardium at least, may be due rather to a paracrine mechanism. The most dramatic developments have been in identifying some of the complex mechanisms underlying the immunosuppressive and nonimmunogenic properties of mesenchymal stromal cells which have important implications for the management of conditions like acute graft-versus-host disease. SUMMARY: Mesenchymal stromal cells are a biologically important cell population that are able to support hematopoiesis, can differentiate along mesenchymal and nonmesenchymal lineages in vitro, are capable of suppressing alloresponses and appear to be nonimmunogenic. These properties suggest emerging roles for mesenchymal stromal cells in cell therapy.

Animals↗

PubMed2004

Sensory hair cell death and regeneration: two halves of the same equation.

PURPOSE OF REVIEW: Sensory hair cells are susceptible to ototoxic damage from a variety of sources, including antibiotic treatment. Unfortunately, this often results in permanent hearing and/or balance problems in humans. By understanding how sensory hair cells die in response to aminoglycoside treatment, preventive strategies may be developed. This review will discuss some of the key recent findings in sensory hair cell death and regeneration. RECENT FINDINGS: Aminoglycosides induce hair cell death through the initiation of apoptosis. Early and late stages of hair cell apoptosis have been defined, and several of the key molecules involved in the cascade have been identified. Moreover, specific inhibitors of apoptosis rescue hair cells from death and preserve function. Hair cell death has been shown to induce regeneration through supporting cell transdifferentiation, proliferation, and new hair cell differentiation in birds and lower vertebrates. Regeneration in the mammalian cochlea does not occur spontaneously, but genetic manipulation of cell cycle genes, induction of new hair cells through gene therapy, and introduction of stem cells into damaged cochleas suggest that repair and replacement of lost hair cells in the organ of Corti may be possible. Finally, continuing investigations of the mouse, zebrafish, and human genomes may one day enable manipulation of the cochlea so that functional regeneration is readily available as a therapeutic intervention. SUMMARY: The discovery that hair cells can regenerate in birds and other nonmammalian vertebrates has fueled a wide range of studies to find ways to restore hearing and balance in mammals. The demonstration that apoptosis and proliferation are coupled as controlling factors in regeneration and the advent of new approaches such as gene therapy, stem cell transplantation, and genomics may lead to methods for inducing hair cell regeneration and repair in the mammalian cochlear and vestibular systems.

Aminoglycosides↗