Biomedical subjects

Kimberly J Riehle

Publications and source records attributed to Kimberly J Riehle.

5 recordsLinked to original sources

PubMed2006

Distinct Wnt signaling pathways have opposing roles in appendage regeneration.

In contrast to mammals, lower vertebrates have a remarkable capacity to regenerate complex structures damaged by injury or disease. This process, termed epimorphic regeneration, involves progenitor cells created through the reprogramming of differentiated cells or through the activation of resident stem cells. Wnt/beta-catenin signaling regulates progenitor cell fate and proliferation during embryonic development and stem cell function in adults, but its functional involvement in epimorphic regeneration has not been addressed. Using transgenic fish lines, we show that Wnt/beta-catenin signaling is activated in the regenerating zebrafish tail fin and is required for formation and subsequent proliferation of the progenitor cells of the blastema. Wnt/beta-catenin signaling appears to act upstream of FGF signaling, which has recently been found to be essential for fin regeneration. Intriguingly, increased Wnt/beta-catenin signaling is sufficient to augment regeneration, as tail fins regenerate faster in fish heterozygous for a loss-of-function mutation in axin1, a negative regulator of the pathway. Likewise, activation of Wnt/beta-catenin signaling by overexpression of wnt8 increases proliferation of progenitor cells in the regenerating fin. By contrast, overexpression of wnt5b (pipetail) reduces expression of Wnt/beta-catenin target genes, impairs proliferation of progenitors and inhibits fin regeneration. Importantly, fin regeneration is accelerated in wnt5b mutant fish. These data suggest that Wnt/beta-catenin signaling promotes regeneration, whereas a distinct pathway activated by wnt5b acts in a negative-feedback loop to limit regeneration.

Adult Stem Cells↗

PubMed2006

Proinflammatory cytokine production in liver regeneration is Myd88-dependent, but independent of Cd14, Tlr2, and Tlr4.

TNF and IL-6 are considered to be important to the initiation or priming phase of liver regeneration. However, the signaling pathways that lead to the production of these cytokines after partial hepatectomy (PH) have not been identified. Enteric-derived LPS appears to be important to liver regeneration, possibly by stimulating proinflammatory cytokine production after surgery. To determine whether LPS signaling pathways are involved in the regulation of the proinflammatory cytokines TNF and IL-6 during the priming phase of liver regeneration, we performed PH on mice lacking the TLRs Tlr4 and Tlr2, the LPS coreceptor, Cd14, and Myd88, an adapter protein involved in most TLR and IL-1R pathways. In MyD88 knockout (KO) mice after PH, both liver Tnf mRNA and circulating IL-6 levels were severely depressed compared with heterozygous or wild-type mice. Activation of STAT-3 and three STAT-3 responsive genes, Socs3, Cd14, and serum amyloid A2 were also blocked. In contrast, Tlr4, Tlr2, and Cd14 KO mice showed no deficits in the production of IL-6. Surprisingly, none of these KO mice showed any delay in hepatocyte replication. These data indicate that the LPS receptor TLR4, as well as TLR2 and CD14, do not play roles in regulating cytokine production or DNA replication after PH. In contrast, MyD88-dependent pathways appear to be responsible for TNF, IL-6, and their downstream signaling pathways.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Liver regeneration.

During liver regeneration after partial hepatectomy, normally quiescent hepatocytes undergo one or two rounds of replication to restore the liver mass by a process of compensatory hyperplasia. A large number of genes are involved in liver regeneration, but the essential circuitry required for the process may be categorized into three networks: cytokine, growth factor and metabolic. There is much redundancy within each network, and intricate interactions exist between them. Thus, loss of function from a single gene rarely leads to complete blockage of liver regeneration. The innate immune system plays an important role in the initiation of liver regeneration after partial hepatectomy, and new cytokines and receptors that participate in initiation mechanisms have been identified. Hepatocytes primed by these agents readily respond to growth factors and enter the cell cycle. Presumably, the increased metabolic demands placed on hepatocytes of the regenerating liver are linked to the machinery needed for hepatocyte replication, and may function as a sensor that calibrates the regenerative response according to body demands. In contrast to the regenerative process after partial hepatectomy, which is driven by the replication of existing hepatocytes, liver repopulation after acute liver failure depends on the differentiation of progenitor cells. Such cells are also present in chronic liver diseases, but their contribution to the production of hepatocytes in those conditions is unknown. Most of the new knowledge about the molecular and cellular mechanisms of liver regeneration is both conceptually important and directly relevant to clinical problems.

Animals↗

PubMed2005

Mechanisms of liver regeneration and their clinical implications.

During the last few years there have been major advances in the understanding of the mechanisms of liver regeneration. These advances derived to a great extent from the increased use of transgenic and knockout mice. In parallel with the experimental work, human partial liver transplantation from cadavers and living donors continues to increase, stimulating hepatologists and surgeons to learn more about the mechanisms that regulate and promote regeneration. Thus, knowledge generated from laboratory work in rodents can be applied to clinical problems, while data on human transplantation can also guide the design of experimental work. In this review, we discuss a few selected aspects of liver regeneration that are of interest in both the laboratory and the clinic.

Animals↗

PubMed2004

A prospective study of a focused, surgeon-performed ultrasound examination for the detection of occult common femoral vein thrombosis in critically ill patients.

HYPOTHESIS: A focused, surgeon-performed ultrasound examination of the common femoral veins is an accurate screening tool for the detection of common femoral vein thrombosis in high-risk, critically ill patients. DESIGN: A prospective study using a focused ultrasound examination for findings consistent with deep vein thrombosis of the common femoral veins. The results of these examinations were compared with those of duplex imaging or computed tomographic venography studies. SETTING: Surgical intensive care unit. PATIENTS: All critically ill patients who were admitted to the surgical intensive care unit and considered to be at high risk for the development of deep vein thrombosis. MAIN OUTCOME MEASURE: Presence of deep vein thrombosis in the common femoral veins. RESULTS: During a 16-month period, surgeons performed 306 ultrasound examinations on 220 critically ill surgical patients. The results included 295 true negative, 9 true positive, 1 false negative, and 1 false positive, yielding a 90.0% sensitivity, 99.6% specificity, and 99.3% accuracy. CONCLUSION: A focused, surgeon-performed ultrasound examination is a rapid and accurate screening method to detect common femoral vein thrombosis in critically ill patients as well as to examine those patients in whom pulmonary embolism is strongly suspected.

Adult↗