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PubMed2003

The potential of stem cells.

UNLABELLED: Although stem cells have held the fascination of scientists for years, the attention of the general public has recently been captured by the derivation of human embryonic stem cells. In this review we describe the historical experiments leading up to the isolation of human embryonic stem cells and discuss recent advances in our understanding of both embryonic and somatic stem cells. Select examples are used to illustrate the potential of stem cells, both in the sense of their ability to differentiate into specific cell types and in the sense of their power to treat various diseases and conditions. Also discussed are recent studies describing current progress toward the treatment of Parkinson disease, spinal cord injuries, diabetes, and cardiac disease. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader will be able to describe the various types of stem cells, outline potential clinical uses of stem cells, and summarize the somatic cell transdifferentiation debate.

Cell Differentiation↗
PubMed2003

Hepatoid carcinoma of the ovary: a report of three cases admixed with a common surface epithelial carcinoma.

Hepatoid carcinoma of the ovary is an ovarian carcinoma that has phenotypic properties in common with hepatocellular carcinomas. However, the extent of the tumor cells' similarity to and their difference from hepatocytes is largely unknown. In addition, the precursor cell of origin for hepatoid carcinoma of the ovary has not been identified. Three cases of alpha-fetoprotein-producing hepatoid carcinoma of the ovary that were admixed with an adenocarcinoma of common surface epithelial type are reported. The hepatoid carcinomas had a trabecular architecture with canaliculi detected by polyclonal (but not monoclonal) anticarcinoembryonic antigen antibodies. A hepatic phenotype in the hepatoid tumor cells was further supported by the production of albumin mRNA by in situ hybridization. The adenocarcinomas in the three cases were mucinous (Case 1), serous (Case 2), and endometrioid (Case 3), respectively. The cytokeratin (CK) profile in both the hepatoid and adenocarcinomatous components was CK18+/CK19+/CK20+/-, whereas normal and neoplastic hepatocytes were CK18+/CK19-/CK20-. Although this study supports a hepatic phenotype in ovarian hepatoid carcinoma, the CK profile of hepatoid carcinoma differs from that of normal and neoplastic hepatocytes but resembles that of the associated common epithelial adenocarcinoma. These findings suggest that hepatoid carcinoma of the ovary is probably derived from carcinomas of surface epithelial origin by a process of neometaplasia or transdifferentiation.

Adenocarcinoma↗
PubMed2005

The potential of adipose-derived adult stem cells as a source of neuronal progenitor cells.

Adipose-derived adult stem cells are a population of mesenchymal stem cells extracted from discarded adipose tissue. Many have reported the differentiation of adipose-derived stem cells into chondrocytes, myocytes, osteoblasts, and, most recently, neural progenitor cells. This article covers the current state of the potential of the differentiation of adipose-derived stem cells into neuronal cells and an overview of their potential as adult stem therapies for neurological disorders. It has been reported that adipose-derived stem cells are capable of undergoing neuronal differentiation using protocols similar to that of Woodbury et al., which reported the differentiation of bone marrow stromal cells specifically into neurons. However, the transdifferentiation of bone marrow stromal cells into neuronal cells has recently fallen under intense criticism, which will likely place the plasticity of adipose-derived stem cells under scrutiny as well. To date, no group has produced evidence that adipose-derived stem cells are capable of differentiating to mature, functional neuronal cells in vitro. However, recent in vivo studies with adipose-derived stem cells are promising.

Adipocytes↗
PubMed2004

Polymorphonuclear neutrophils in posttraumatic osteomyelitis: cells recovered from the inflamed site lack chemotactic activity but generate superoxides.

The pathogenesis of posttraumatic osteomyelitis, one of the major complications after orthopedic surgery, is not yet understood. Formation of bacterial biofilms on the implant is presumed, conferring resistance to antibiotic therapy and probably also to the host defense mechanisms. In that context, the polymorphonuclear neutrophils (PMN) having infiltrated the infected site were recovered and characterized phenotypically and functionally. Loss of CD62L and upregulation of CD14 were seen, as was expression of CD83. Expression of the latter is dependent on de novo protein synthesis and thus is indicative of an extended life span and a transdifferentiation of the PMN at the infected site. The infiltrated PMN had lost their chemotactic activity, whereas the capacity to produce superoxides was preserved and in some patients even enhanced. In vitro experiments done in parallel showed that long-term culture with interferon-gamma resulted in similar alterations of PMN: loss of chemotactic activity, whereas other functions of PMN, such generation of superoxides and phagocytosis of opsonized bacteria, were preserved or even enhanced. The loss of the migratory capacity of PMN having already emigrated from the blood vessel to the infected site is not expected to affect the host defense negatively. Assuming, however, that bacteria are organized as a biofilm and that infiltration into this biofilm is required for phagocytosis of the bacteria, our data could to some extent explain why despite being activated, the PMN are not able to control the infection. By releasing their cytotoxic, proteolytic, and collagenolytic potential, PMN might instead contribute to tissue destruction and eventually to osteolysis.

Adult↗
PubMed2006

Influence of stem cell mobilization and liver regeneration on hepatic parenchymal chimerism in the rat.

BACKGROUND: Despite the newly discovered plasticity of hematopoietic stem cells, their capacity to "transdifferentiate" into parenchymal cells and the regulation of this process is not yet elucidated. The present study was designed to investigate the effect of stem cell mobilization and liver regeneration on this process using a syngeneic rat female-to-male liver transplantation model. METHODS: Rate and frequency of Y-chromosome containing hepatocytes was determined by fluorescence-in situ hybridization (FISH) using a rat Y-chromosome specific probe. Rats were subjected to full-size or partial liver transplantation with and without stem cell mobilization using granulocyte colony stimulating factor (G-CSF). The effect of stem cell mobilization was confirmed by assessing the white blood count and by evaluating the migration of granulopoietic precursor cells to the liver. RESULTS: Treatment with G-CSF induced a twofold increase of peripheral white blood cells and a strong influx of granulopoietic precursor cells into the liver. Transplantation of a partial liver graft was followed by a 90% recovery of the original liver weight within a week, demonstrating the strong regenerative stimulus. Irrespective of the experimental model, the incidence and rate of Y-chromosome containing hepatocytes never exceeded 0.77%. CONCLUSION: Neither stem cell mobilization nor liver regeneration enhanced the incidence or rate of stem cell derived hepatocytes in a liver graft with unimpaired regenerative potential.

Animals↗
PubMed2003

Participation of bone marrow-derived cells in long-term repair processes after experimental stroke.

Bone marrow-derived cells participate in remodeling processes of many ischemia-associated diseases, which has raised hopes for the use of bone marrow as a source for cell-based therapeutic approaches. To study the participation of bone marrow-derived cells in a stroke model, bone marrow from C57BL/6-TgN(ACTbEGFP)1Osb mice that express green fluorescent protein (GFP) in all cells was transplanted into C57BL/6J mice. The recipient mice underwent permanent occlusion of the middle cerebral artery, and bone marrow-derived cells were tracked by fluorescence. The authors investigated the involvement of bone marrow-derived cells in repair processes 6 weeks and 6 months after infarction. Six weeks after occlusion of the artery, more than 90% of the GFP-positive cells in the infarct border zone were microglial cells. Very few GFP-positive cells expressed endothelial markers in the infarct/infarct border zone, and no bone marrow-derived cells transdifferentiated into astrocytes, neurons, or oligodendroglial cells at all time points investigated. The results indicate the need for additional experimental studies to determine whether therapeutic application of nonselected bone marrow will replenish brain cells beyond an increase in microglial engraftment.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2004

A critical role for thrombin in vertebrate lens regeneration.

Lens regeneration in urodele amphibians such as the newt proceeds from the dorsal margin of the iris where pigment epithelial cells (PEC) re-enter the cell cycle and transdifferentiate into lens. A general problem in regeneration research is to understand how the events of tissue injury or removal are coupled to the activation of plasticity in residual differentiated cells or stem cells. Thrombin, a pivotal regulator of the injury response, has been implicated as a regulator of cell cycle re-entry in newt myotubes, and also in newt iris PEC. After removal of the lens, thrombin was activated on the dorsal margin for 5-7 days. Inactivation of thrombin by either of two different inhibitors essentially blocked S-phase re-entry by PEC at this location. The axolotl, a related species which can regenerate its limb but not its lens, can activate thrombin after amputation but not after lens removal. These data support the hypothesis that thrombin is a critical signal linking injury to regeneration, and offer a new perspective on the evolutionary and phylogenetic questions about regeneration.

Ambystoma↗
PubMed2002

The tao of hematopoietic stem cells: toward a unified theory of tissue regeneration.

Hematopoietic stem cells (HSCs) are the best studied of the tissue-specific stem cells. By definition, HSCs have long been regarded as restricted to formation of blood cells of both the lymphoid and myeloid lineages. HSCs residing in the bone marrow microenvironment have self-renewal capacity and can repopulate the hematopoietic system of irradiated transplant recipients for the lifetime of the individual. Therefore, HSCs are extremely important targets for gene therapy applications aimed toward the treatment of inherited and acquired blood disorders. However, recent studies have suggested that a subpopulation of HSCs may have the ability to contribute to diverse cell types such as hepatocytes, myocytes, and neuronal cells, especially following induced tissue damage. Preclinical amelioration of liver disease and myocardial infarcts by HSC-enriched bone marrow cell populations raises the possibility that HSC transplants have the potential to provide therapeutic benefit for a wide variety of diseases. These surprising findings contradict the dogma that adult stem cells are developmentally restricted. Extrapolation of these findings to the clinic will be facilitated by prospective identification of the stem cells that possess this developmental plasticity. Furthermore, characterization of the signaling pathways and molecular determinants regulating the remarkable transdifferentiation capacity of these stem cells may provide insight into novel approaches for modulating frequency of differentiative potential.

Animals↗
PubMed2005

Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation.

Overexpression of the type II transmembrane serine protease matriptase is a highly consistent feature of human epithelial tumors. Here we show that matriptase possesses a strong oncogenic potential when unopposed by its endogenous inhibitor, HAI-1. Modest orthotopic overexpression of matriptase in the skin of transgenic mice caused spontaneous squamous cell carcinoma and dramatically potentiated carcinogen-induced tumor formation. Matriptase-induced malignant conversion was preceded by progressive interfollicular hyperplasia, dysplasia, follicular transdifferentiation, fibrosis, and dermal inflammation. Furthermore, matriptase induced activation of the pro-tumorigenic PI3K-Akt signaling pathway. This activation was frequently accompanied by H-ras or K-ras mutations in carcinogen-induced tumors, whereas matriptase-induced spontaneous carcinoma formation occurred independently of ras activation. Increasing epidermal HAI-1 expression completely negated the oncogenic effects of matriptase. The data implicate dysregulated matriptase expression in malignant epithelial transformation.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2005

Transcription switches for protoxylem and metaxylem vessel formation.

Land plants evolved xylem vessels to conduct water and nutrients, and to support the plant. Microarray analysis with a newly established Arabidopsis in vitro xylem vessel element formation system and promoter analysis revealed the possible involvement of some plant-specific NAC-domain transcription factors in xylem formation. VASCULAR-RELATED NAC-DOMAIN6 (VND6) and VND7 can induce transdifferentiation of various cells into metaxylem- and protoxylem-like vessel elements, respectively, in Arabidopsis and poplar. A dominant repression of VND6 and VND7 specifically inhibits metaxylem and protoxylem vessel formation in roots, respectively. These findings suggest that these genes are transcription switches for plant metaxylem and protoxylem vessel formation.

Arabidopsis Proteins↗
PubMed2001

Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice.

Chondrocyte hypertrophy is a mandatory step during endochondral ossification. Cbfa1-deficient mice lack hypertrophic chondrocytes in some skeletal elements, indicating that Cbfa1 may control hypertrophic chondrocyte differentiation. To address this question we generated transgenic mice expressing Cbfa1 in nonhypertrophic chondrocytes (alpha1(II) Cbfa1). This continuous expression of Cbfa1 in nonhypertrophic chondrocytes induced chondrocyte hypertrophy and endochondral ossification in locations where it normally never occurs. To determine if this was caused by transdifferentiation of chondrocytes into osteoblasts or by a specific hypertrophic chondrocyte differentiation ability of Cbfa1, we used the alpha1(II) Cbfa1 transgene to restore Cbfa1 expression in mesenchymal condensations of the Cbfa1-deficient mice. The transgene restored chondrocyte hypertrophy and vascular invasion in the bones of the mutant mice but did not induce osteoblast differentiation. This rescue occurred cell-autonomously, as skeletal elements not expressing the transgene were not affected. Despite the absence of osteoblasts in the rescued animals there were multinucleated, TRAP-positive cells resorbing the hypertrophic cartilage matrix. These results identify Cbfa1 as a hypertrophic chondrocyte differentiation factor and provide a genetic argument for a common regulation of osteoblast and chondrocyte differentiation mediated by Cbfa1.

Animals↗
PubMed2002

Novel insight into vascular, stress, and auxin-dependent and -independent gene expression programs in strawberry, a non-climacteric fruit.

Using cDNA microarrays, a comprehensive investigation of gene expression was carried out in strawberry (Fragaria x ananassa) fruit to understand the flow of events associated with its maturation and non-climacteric ripening. We detected key processes and novel genes not previously associated with fruit development and ripening, related to vascular development, oxidative stress, and auxin response. Microarray analysis during fruit development and in receptacle and seed (achene) tissues established an interesting parallelism in gene expression between the transdifferentiation of tracheary elements in Zinnia elegans and strawberry. One of the genes, CAD, common to both systems and encoding the lignin-related protein cinnamyl alcohol dehydrogenase, was immunolocalized to immature xylem cells of the vascular bundles in the strawberry receptacle. To examine the importance of oxidative stress in ripening, gene expression was compared between fruit treated on-vine with a free radical generator and non-treated fruit. Of 46 genes induced, 20 were also ripening regulated. This might suggest that active gene expression is induced to cope with oxidative stress conditions during ripening or that the strawberry ripening transcriptional program is an oxidative stress-induced process. To gain insight into the hormonal control of non-climacteric fruit ripening, an additional microarray experiment was conducted comparing gene expression in fruit treated exogenously with auxin and control fruit. Novel auxin-dependent genes and processes were identified in addition to transcriptional programs acting independent of auxin mainly related to cell wall metabolism and stress response.

Alcohol Oxidoreductases↗
PubMed2005

A RING domain gene is expressed in different cell types of leaf trace, stem, and juvenile bundles in the stem vascular system of zinnia.

The in vitro zinnia (Zinnia elegans) mesophyll cell system, in which leaf mesophyll cells are induced to transdifferentiate into tracheary elements with high synchrony, has become an established model for studying xylogenesis. The architecture of the stem vascular system of zinnia cv Envy contains three anatomically distinct vascular bundles at different stages of development. Juvenile vascular strands of the subapical region develop into mature vascular strands with leaf trace segments and stem segments. Characteristic patterns of gene expression in juvenile, leaf trace, and stem bundles are revealed by a molecular marker, a RING domain-encoding gene, ZeRH2.1, originally isolated from a zinnia cDNA library derived from differentiating in vitro cultures. Using RNA in situ hybridization, we show that ZeRH2.1 is expressed preferentially in two specific cell types in mature zinnia stems. In leaf trace bundles, ZeRH2.1 transcript is abundant in xylem parenchyma cells, while in stem bundles it is abundant in phloem companion cells. Both of these cell types show wall ingrowths characteristic of transfer cells. In addition, ZeRH2.1 transcript is abundant in some phloem cells of juvenile bundles and in leaf palisade parenchyma. The complex and developmentally regulated expression pattern of ZeRH2.1 reveals heterogeneity in the vascular anatomy of the zinnia stem. We discuss a potential function for this gene in intercellular transport processes.

Amino Acid Sequence↗
PubMed2002

Early gene expression associated with the commitment and differentiation of a plant tracheary element is revealed by cDNA-amplified fragment length polymorphism analysis.

Isolated mesophyll cells from Zinnia elegans are induced by auxin and cytokinin to form tracheary elements (TEs) in vitro with high synchrony. To reveal the changing patterns of gene expression during the 48 h of transdifferentiation from mesophyll to TE cell fate, we used a cDNA-amplified fragment length polymorphism approach to generate expression profiles of >30,000 cDNA fragments. Transcriptional changes of 652 cDNA fragments were observed, of which 304 have no previously described function or sequence identity. Sixty-eight genes were upregulated within 30 min of induction and represent key candidates for the processes that underlie the early stages of commitment and differentiation to a TE cell fate.

Asteraceae↗
PubMed1993

Dermal-epidermal interactions--follicle-derived cell populations in the study of hair-growth mechanisms.

All skin appendage development is initiated by a series of dermal-epidermal interactions. These continue to underpin adult hair follicle activities through the specialized follicular cell populations--indeed the inductive properties of isolated dermal papillae from adult vibrissa follicles are well established. Far less is known about the influence of adult follicle epidermis on dermal cells, or inductive properties of papilla cells from other follicle types. Cultured papilla cells, unusually, are able to support the proliferation of skin epidermal cells during simple association in culture, but do not produce more elaborate organization or differentiation. However, germinative epidermal cells from the follicle base are morphologically and behaviorally distinct from other epidermal populations, and in simple association with papilla cells interact to form complex structures with a distinct basal lamina. That hair follicle germinative cells have an important influence on dermal cells is further demonstrated by in vivo recombinations, where germinative cells interact with otherwise non-inductive follicle dermal sheath cells to initiate follicle formation and hair growth. In vitro, several follicle cell populations assembled within the capsule of a vibrissa follicle and grown in a three-dimensional culture system produce hair-type fibers. When cultured pelage follicle dermal papilla cells are implanted alone into footpad skin under controlled conditions, new pelage-type follicles and fibers are induced. This emphasizes the power and universal nature of inductive influences from papilla cells, and underlines the dermatologic potential of cell manipulations. The transdifferentiation of the footpad epidermis is a powerful biologic phenomenon normally only seen in embryonic-type association experiments.

Aging↗
PubMed2004

Smad3 as a mediator of the fibrotic response.

Transforming growth factor-beta (TGF-beta) plays a central role in fibrosis, contributing to the influx and activation of inflammatory cells, the epithelial to mesenchymal transdifferentiation (EMT) of cells and the influx of fibroblasts and their subsequent elaboration of extracellular matrix. TGF-beta signals through transmembrane receptor serine/threonine kinases to activate novel signalling intermediates called Smad proteins, which modulate the transcription of target genes. The use of mice with a targeted deletion of Smad3, one of the two homologous proteins which signals from TGF-beta/activin, shows that most of the pro-fibrotic activities of TGF-beta are mediated by Smad3. Smad3 null inflammatory cells and fibroblasts do not respond to the chemotactic effects of TGF-beta and do not autoinduce TGF-beta. The loss of Smad3 also interferes with TGF-beta-mediated induction of EMT and genes for collagens, plasminogen activator inhibitor-1 and the tissue inhibitor of metalloprotease-1. Smad3 null mice are resistant to radiation-induced cutaneous fibrosis, bleomycin-induced pulmonary fibrosis, carbon tetrachloride-induced hepatic fibrosis as well as glomerular fibrosis induced by induction of type 1 diabetes with streptozotocin. In fibrotic conditions that are induced by EMT, such as proliferative vitreoretinopathy, ocular capsule injury and glomerulosclerosis resulting from unilateral ureteral obstruction, Smad3 null mice also show an abrogated fibrotic response. Animal models of scleroderma, cystic fibrosis and cirrhosis implicate involvement of Smad3 in the observed fibrosis. Additionally, inhibition of Smad3 by overexpression of the inhibitory Smad7 protein or by treatment with the small molecule, halofuginone, dramatically reduces responses in animal models of kidney, lung, liver and radiation-induced fibrosis. Small moleucule inhibitors of Smad3 may have tremendous clinical potential in the treatment of pathological fibrotic diseases.

Animals↗
PubMedDate not supplied

Effects of a CDK inhibitor on lens regeneration.

Lens regeneration in adult newts is always initiated from the dorsal iris by transdifferentiation of the pigment epithelial cells. One of the most important early events should be the ability of pigment epithelial cells to dedifferentiate and re-enter the cell cycle. As a first step in an attempt to study this event, we have decided to examine the effects of a cyclin-dependent kinase-2 inhibitor on lens regeneration. At the appropriate concentration, this inhibitor completely abolished the ability of pigment epithelial cells to form a new lens, but it did not stop them from dedifferentiating and forming a small lens vesicle. The effects of this inhibitor seem to be mediated by its opposite effects on cell proliferation and apoptosis. The inhibitor significantly reduced cell proliferation and enhanced apoptosis of pigment epithelial cells both in vitro and in vivo and of the regenerating lens in vivo.

Animals↗
PubMed2004

Corneal epithelial stem cells: past, present, and future.

Corneal epithelium is a self-renewing tissue. Recent studies indicate that corneal epithelial stem cells reside preferentially in the basal layer of peripheral cornea in the limbal zone, rather than uniformly in the entire corneal epithelium. This idea is supported by a unique limbal/corneal expression pattern of the K3 keratin marker for corneal-type differentiation; the preferential distribution of the slow-cycling (label-retaining) cells in the limbus; the superior proliferative capacity of limbal cells as compared with central corneal epithelial cells in vitro and in vivo; and the ability of limbal basal cells to rescue/reconstitute severely damaged or completely depleted corneal epithelium upon transplantation. The limbal/stem cell concept provides explanations for several paradoxical properties of corneal epithelium including the predominance of tumor formation in the limbal zone, the centripetal migration of peripheral corneal cells toward the central cornea, and the "mature-looking" phenotype of the corneal basal cells. The limbal stem cell concept has led to a better understanding of the strategies that a stratified squamous epithelium uses in repair, to a new classification of various anterior surface epithelial diseases, to a repudiation of the classical idea of "conjunctival transdifferentiation", and to a new surgical procedure called limbal stem cell transplantation.

Animals↗