Mitogenic effects of hepatic stimulator substance on cultured nonparenchymal liver epithelial cells

M.D., M.R.C.P. Sanjeev Gupta; LaBrecque, Douglas R.; Shafritz, David A.

doi:10.1002/hep.1840150322

Cited by 36 publications

(24 citation statements)

References 32 publications

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“…After 72 hours, 1 Ci 3 H-thymidine was added for 1 hour, and incorporation of thymidine into DNA was analyzed as previously described. 19 Statistical Analysis. Data are presented as the mean Ϯ SD.…”

Section: Methodsmentioning

confidence: 99%

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Joseph

Gupta

2006

Hepatology

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Successful grafting of tissues or cells from mismatched donors requires systemic immunosuppression.It is yet to be determined whether immunosuppressive manipulations perturb transplanted cell engraftment or proliferation. We used syngeneic and allogeneic cell transplantation assays based on F344 recipient rats lacking dipeptidyl peptidase IV enzyme activity to identify transplanted hepatocytes. Immunosuppressive drugs used were tacrolimus (a calcineurin inhibitor) and its synergistic partners, rapamycin (a regulator of the mammalian target of rapamycin [mTOR]) and mycophenolate mofetil (an inosine monophosphate dehydrogenase inhibitor). First, suitable drug doses capable of inducing longterm survival of allografted hepatocytes were identified. In pharmacologically effective doses, rapamycin enhanced cell engraftment by downregulating hepatic expression of selected inflammatory cytokines but profoundly impaired proliferation of transplanted cells, which was necessary for liver repopulation. In contrast, tacrolimus and/or mycophenolate mofetil perturbed neither transplanted cell engraftment nor their proliferation. Therefore, mTOR-dependent extracellular and intracellular mechanisms affected liver replacement with transplanted cells. In conclusion, insights into the biological effects of specific drugs on transplanted cells are critical in identifying suitable immunosuppressive strategies for cell therapy. (HEPATOLOGY 2006;44:410-419.)

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Section: Methodsmentioning

confidence: 99%

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Joseph

Gupta

2006

Hepatology

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“…Two hours later, drugs affecting potassium channel activity or vehicle alone was added to cultured cells. Primary rat hepatocytes were cultured with and without 10 ng/ml hHGF and incubated with drugs for 44 -46 h. HepG2, HuH-7, and HFL cells were cultured for 22-23 h. This was followed by the addition of 1 Ci of [ 3 H]thymidine (Sigma) for 1 h. Cells were washed twice with ice-cold phosphate-buffered saline, and trichloroacetic acid-precipitable DNA was extracted as described previously (29). [ 3 H]Thymidine incorporation into DNA was measured by liquid scintillation counting with normalization to DNA content.…”

Section: Methodsmentioning

confidence: 99%

KATP Channels Regulate Mitogenically Induced Proliferation in Primary Rat Hepatocytes and Human Liver Cell Lines

Malhi¹,

Irani²,

Rajvanshi³

et al. 2000

Journal of Biological Chemistry

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To determine whether K ATP channels control liver growth, we used primary rat hepatocytes and several human cancer cell lines for assays. K ATP channel openers (minoxidil, cromakalim, and pinacidil) increased cellular DNA synthesis, whereas K ATP channel blockers (quinidine and glibenclamide) attenuated DNA synthesis. The channel inhibitor glibenclamide decreased the clonogenicity of HepG2 cells without inducing cytotoxicity or apoptosis. To demonstrate the specificity of drugs for K ؉ channels, whole-cell patch-clamp recordings were made. Hepatocytes revealed K ؉ currents with K ATP channel properties. These K ؉ currents were augmented by minoxidil and pinacidil and attenuated by glibenclamide as well as tetraethylammonium, in agreement with established responses of K ATP channels. Reverse transcription of total cellular RNA followed by polymerase chain reaction showed expression of K ATP channel-specific subunits in rat hepatocytes and human liver cell lines. Calcium fluxes were unperturbed in glibenclamide-treated HepG2 cells and primary rat hepatocytes following induction with ATP and hepatocyte growth factor, respectively, suggesting that the effect of K ATP channel activity upon hepatocyte proliferation was not simply due to indirect modulation of intracellular calcium. The regulation of mitogen-related hepatocyte proliferation by K ATP channels advances our insights into liver growth control. The findings have implications in mechanisms concerning liver development, regeneration, and oncogenesis.

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“…Many studies have shown the potential of stem cells to differentiate toward hepatocytes. Human mesenchymal stem cells (hMSCs) [8] as well as human embryonic stem cells (hESC) [9], liver stem cells/oval cells [10], cord blood cells [11], bone marrow stem cells [12] and fetal hepatocytes [13] are stem cell types that display potential to develop into hepatocytes. Bone marrow represents an abundant and accessible source of adult stem cells that can differentiate along multiple lineage pathways, including the hepatic lineage [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…Other advantages of using mesenchymal stem cells in tissue regenerative medicine include their ease of isolation, proliferative capacity, efficiency of in vitro transfection and the potential use of autologous cells [7]. Many studies have shown the potential of stem cells to differentiate toward hepatocytes [8][9][10][11][12][13]. The traditional concept of stem cell-based therapy consists of the isolation of stem cells from patients, expansion and differentiation in vitro, and subsequent re-transplantation of autologous cells into the patient.…”

Section: Introductionmentioning

confidence: 99%

Hepatic differentiation from human mesenchymal stem cells on a novel nanofiber scaffold

Ghaedi¹,

Soleimani

Shabani

et al. 2012

Cellular and Molecular Biology Letters

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Abstract:The emerging fields of tissue engineering and biomaterials have begun to provide potential treatment options for liver failure. The goal of the present study is to investigate the ability of a poly L-lactic acid (PLLA) nanofiber scaffold to support and enhance hepatic differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs). A scaffold composed of poly L-lactic acid and collagen was fabricated by the electrospinning technique. After characterizing isolated hMSCs, they were seeded onto PLLA nanofiber scaffolds and induced to differentiate into a hepatocyte lineage. The mRNA levels and protein expression of several important hepatic genes were determined using RT-PCR, immunocytochemistry and ELISA. Flow cytometry revealed that the isolated bone marrow-derived stem cells were positive for hMSC-specific markers CD73, CD44, CD105 and CD166 and negative for hematopoietic markers CD34 and CD45. The differentiation of these stem cells into adipocytes and osteoblasts demonstrated their multipotency. Scanning electron microscopy showed adherence of cells in the nanofiber scaffold during differentiation towards hepatocytes. Our results showed that expression levels of liver-specific markers such as albumin, α-fetoprotein, and cytokeratins 8 and 18 were higher in differentiated cells on the nanofibers than when cultured on plates. Importantly, liver functioning serum proteins, albumin and α-1 antitrypsin were secreted into the culture medium at higher levels by the differentiated cells on the nanofibers than on the plates, demonstrating that our nanofibrous scaffolds promoted and enhanced hepatic differentiation under our culture conditions. Our results show that the engineered PLLA nanofibrous scaffold is a conducive matrix for the differentiation of MSCs into functional hepatocyte-like cells. This represents the first step for the use of this nanofibrous scaffold for culture and differentiation of stem cells that may be employed for tissue engineering and cell-based therapy applications.

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Mitogenic effects of hepatic stimulator substance on cultured nonparenchymal liver epithelial cells

Cited by 36 publications

References 32 publications

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

KATP Channels Regulate Mitogenically Induced Proliferation in Primary Rat Hepatocytes and Human Liver Cell Lines

Hepatic differentiation from human mesenchymal stem cells on a novel nanofiber scaffold

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