Matrix metalloproteinases in liver injury, repair and fibrosis.

The liver is a large highly vascularized organ with a central function in metabolic homeostasis, detoxification, and immunity. Due to its roles, the liver is frequently exposed to various insults which can cause cell death and hepatic dysfunction. Alternatively, the liver has a remarkable ability to self-repair and regenerate after injury. Liver injury and regeneration have both been linked to complex extracellular matrix (ECM) related pathways. While normal degradation of ECM components is an important feature of tissue repair and remodeling, irregular ECM turnover contributes to a variety of liver diseases. Matrix metalloproteinases (MMPs) are the main enzymes implicated in ECM degradation. MMPs not only remodel the ECM, but also regulate immune responses. In this review, we highlight some of the MMP-attributed roles in acute and chronic liver injury and emphasize the need for further experimentation to better understand their functions during hepatic physiological conditions and disease progression

Constitutive gene expression and the specification of tissue identity in adult planarian biology

Planarians are flatworms that constitutively maintain adult tissues through cell turnover and can regenerate entire organisms from tiny body fragments. In addition to requiring new cells (from neoblasts), these feats require mechanisms that specify tissue identity in the adult. Crucial roles for Wnt and BMP signaling in the regeneration and maintenance of the body axes have been uncovered, among other regulatory factors. Available data indicate that genes involved in positional identity regulation at key embryonic stages in other animals display persisting regionalized expression in adult planarians. These expression patterns suggest that a constitutively active gene expression map exists for the maintenance of the planarian body. Planarians thus present a fertile ground for the identification of factors regulating the regionalization of the metazoan body plan and for the study of the attributes of these factors that can lead to the maintenance and regeneration of adult tissues.National Institutes of Health (U.S.) (R01GM080639)American Cancer Society (RSG-07-180-01-DDC)W. M. Keck Foundatio

Effects of processes at the population and community level on carbon dynamics of an ecosystem model

Ecological processes at the population and community level are often ignored in biogeochemical models, however, the effects of excluding these processes at the ecosystem level is uncertain. In this study we analyzed the set of behaviors that emerge after introducing population and community processes into an ecosystem carbon model. We used STANDCARB, a hybrid model that incorporates population, community, and ecosystem processes to predict carbon dynamics over time. Our simulations showed that at the population level, colonization and mortality rates can limit the maximum biomass achieved during a successional sequence. Specifically, colonization rates control temporal lags in the initiation of carbon accumulation, and mortality rates can have important effects on annual variation in live biomass. At the community level, differences in species traits and changes in species composition over time introduced significant changes in carbon dynamics. Species with different set of parameters, such as growth and mortality rates, introduce patterns of carbon accumulation that could not be reproduced using a single species with the average of parameters of multiple species or by simulating the most abundant species (strategies commonly employed in terrestrial biogeochemical models). We conclude that omitting population and community processes from biogeochemical models introduces an important source of uncertainty that can impose important limitations for predictions of future carbon balances

GLAND CELLS IN HYDRA

The proliferative capacity of gland cells in Hydra attenuata was investigated. The results indicate that both gland cell proliferation and interstitial cell differentiation to gland cells contribute to the maintenance of the whole population. On the basis of [3H]thymidine incorporation and nuclear DNA measurements, gland cells consist of at least three different populations. One population consists of rapidly proliferating cells with a cell cycle of about 72 h. These cells are distributed throughout the body column. In the lower gastric region there is a population of non-cycling cells in G2 while in the upper gastric region there is a population of noncycling cells in G1. About half the G1 population becomes a new antigen, SEC 1, which is typical of mucus cells

Limbal stem cell transplantation: clinical results, limits, and perspectives

Limbal stem cell deficiency (LSCD) is a clinical condition characterized by damage of cornea limbal stem cells, which results in an impairment of corneal epithelium turnover and in an invasion of the cornea by the conjunctival epithelium. In these patients, the conjunctivalization of the cornea is associated with visual impairment and cornea transplantation has poor prognosis for recurrence of the conjunctivalization. Current treatments of LSCD are aimed at replacing the damaged corneal stem cells in order to restore a healthy corneal epithelium. The autotransplantation of limbal tissue from the healthy, fellow eye is effective in unilateral LSCD but leads to depauperation of the stem cell reservoir. In the last decades, novel techniques such as cultivated limbal epithelial transplantation (CLET) have been proposed in order to reduce the damage of the healthy fellow eye. Clinical and experimental evidence showed that CLET is effective in inducing long-term regeneration of a healthy corneal epithelium in patients with LSCD with a success rate of 70%-80%. Current limitations for the treatment of LSCD are represented by the lack of a marker able to unequivocally identify limbal stem cells and the treatment of total, bilateral LSCD which requires other sources of stem cells for ocular surface reconstruction

The Establishment and Regulation of Melanocyte Stem Cells in Zebrafish

Stem cells are the cells that regulate the growth and repair of tissues in adult organisms. In this thesis, I sought to develop methodologies to dissect the function and regulation of stem cells during zebrafish melanocyte regeneration. In the first part of this thesis, I develop a drug based method of ablating melanocytes in the adult zebrafish body. The drug is a copper chelator, neocuproine: NCP) that I show causes death specifically of melanocytes in adult, which allows for regeneration from melanocyte stem cells: MSCs). In the next part of the thesis, I employ clonal lineage statistical analyses to study the establishment, recruitment, and proliferation, differentiation, and survival of MSC daughter cells during larval melanocyte regeneration. These analyses suggest that MSCs are likely recruited at random for each regeneration event, and that approximately 84% of MSCs are recruited for any regeneration event. I demonstrate that kit signaling has a greater requirement during larval regeneration than during ontogeny and compare the regeneration of kit heterozygotes to wild type. The mutant heterozygotes have normal MSC recruitment and normal proliferation, differentiation, and survival of daughter cells. The mutant has defective MSC establishment, with this defect being quantitatively sufficient to explain the regeneration defect observed. I then used further clonal lineage analysis to suggest that reduction of kit signaling causes inappropriate differentiation of fated MSCs into ontogenetic melanocytes. These analyses are not unique for comparison of kit mutants to wild type, so can easily be applied to dissect any gene or drug which affects regeneration. In the final part of the thesis, I explore how many spermatagonia form the adult zebrafish male germline. An understanding of this number allows for efficient mutant screens, an essential part of the genetic dissection of any process. The zebrafish has approximately 485 spermatagonia, giving each male approximately 970 genomes which can be mutagenized. This number can be considered during mutant screen designs to eliminate redundant screening