Proline‐mediated enhancement of hepatocyte function in a collagen gel sandwich culture configuration

Lee, Jae-Gwan; Morgan, Jeffrey R.; Tompkins, Ronald G.; Yarmush, Martin L.

doi:10.1096/fasebj.7.6.8472895

Cited by 46 publications

(27 citation statements)

References 10 publications

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“…While embryoid bodies are known to generate three germ layers characteristic of embryo development, many paracrine responses may direct differentiation in those systems. However, in spite of the fact that embryoid bodies were neither included nor induced in our culture configuration, hepatocyte-like cells, or nonparenchymal cell that possibly arise within the cell population during differentiation, may produce auto-regulatory proteins, a phenomenon observed with hepatocytes in a sandwich configuration (Lee et al, 1993). In this case, the alginate may either induce or conserve this resource by limiting the diffusion of endogenously produced extracellular matrix or growth/differentiation inducing proteins.…”

Section: Discussionmentioning

confidence: 98%

Alginate‐PLL microencapsulation: Effect on the differentiation of embryonic stem cells into hepatocytes

Maguire

Novik

Schloss

et al. 2006

Biotech & Bioengineering

147

105

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The emergence of hepatocyte based clinical and pharmaceutical technologies, has been limited by the absence of a stable hepatocyte cell source. Embryonic stem cells may represent a potential solution to this cell source limitation problem since they are highly proliferative, renewable, and pluripotent. Although many investigators have described techniques to effectively differentiate stem cells into a variety of mature cell lineages, their practicality is limited by: (1) low yields of fully differentiated cells, (2) absence of large scale processing considerations, and (3) ineffective downstream enrichment protocols. Thus, a differentiation platform that may be modified to induce and sustain differentiated cell function and scaled to increase differentiated cell yield would improve current stem cell differentiation strategies. Microencapsulation provides a vehicle for the discrete control of key cell culture parameters such as the diffusion of growth factors, metabolites, and wastes. In addition, both cell seeding density and bead composition may be manipulated. In order to assess the feasibility of directing stem cell differentiation via microenvironment regulation, we have developed a murine embryonic stem cell (ES) alginate poly-l-lysine microencapsulation hepatocyte differentiation system. Our results indicate that the alginate microenvironment maintains cell viability, is conducive to ES cell differentiation, and maintains differentiated cellular function. This system may ultimately assist in developing scalable stem cell differentiation strategies.

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Section: Discussionmentioning

confidence: 98%

Alginate‐PLL microencapsulation: Effect on the differentiation of embryonic stem cells into hepatocytes

Maguire

Novik

Schloss

et al. 2006

Biotech & Bioengineering

147

105

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“…24 After serum starvation for 6 hours in 0.1% FBS, hepatocytes were stimulated with and without BMP2 (100 ng/mL), and RNA was harvested 2 hours later.…”

Section: Primary Hepatocyte Culturesmentioning

confidence: 99%

Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice

Steinbicker

Bartnikas

Lohmeyer

et al. 2011

Blood

160

170

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Bone morphogenetic protein (BMP) signaling induces hepatic expression of the peptide hormone hepcidin. Hepcidin reduces serum iron levels by promoting degradation of the iron exporter ferroportin. A relative deficiency of hepcidin underlies the pathophysiology of many of the genetically distinct iron overload disorders, collectively termed hereditary hemochromatosis. Conversely, chronic inflammatory conditions and neoplastic diseases can induce high hepcidin levels, leading to impaired mobilization of iron stores and the anemia of chronic disease. Two BMP type I receptors, Alk2 (Acvr1) and Alk3 (Bmpr1a), are expressed in murine hepatocytes. We report that liver-specific deletion of either Alk2 or Alk3 causes iron overload in mice. The iron overload phenotype was more marked in Alk3-than in Alk2-deficient mice, and Alk3 deficiency was associated with a nearly complete ablation of basal BMP signaling and hepci- IntroductionThe hepatic hormone hepcidin regulates serum iron levels in mice and humans by inducing degradation of the iron exporter, ferroportin. 1,2 Low ferroportin levels reduce intestinal iron absorption and the release of iron from macrophage stores. Human hereditary hemochromatosis is characterized by low hepcidin levels, leading to iron accumulation in liver, heart, and endocrine organs. 1,3 Similarly, hepcidin deficiency causes hepatic iron overload in mice. 2,4 In contrast, high hepcidin levels contribute to the anemia of chronic disease (ACD) by reducing iron bioavailability for erythropoiesis. 5,6 Recent studies have demonstrated a critical role for bone morphogenetic protein (BMP) signaling in the regulation of hepcidin expression by iron. [7][8][9][10][11] Binding of BMP ligands to type I and type II BMP receptors induces the type II receptor to phosphorylate and activate the type I receptor. The activated type I receptor, in turn, phosphorylates intracellular signaling molecules, including SMADs 1, 5, and 8. Phosphorylated SMADs 1, 5, and 8 bind SMAD4 and together translocate to the nucleus, where they activate the expression of genes, including hepcidin and the Id family of transcription factors. 12 Deficiency of Smad4, 10 the BMP coreceptor hemojuvelin, 13,14 or BMP6 15,16 in hepatocytes reduces expression of hepcidin 17,18 and induces iron overload. In addition, BMP signaling appears to have an important role in the induction of hepcidin expression by inflammatory mediators that are involved in ACD. 11,19,20 There are 4 type I BMP receptors: Alk1, Alk2, Alk3, and Alk6. The identity of the type I BMP receptor(s) responsible for iron-dependent signaling and the regulation of hepcidin expression in hepatocytes are unknown. Alk1 is predominantly expressed in the endothelium. Alk6 is expressed at low levels in murine liver, 21 and global Alk6 deficiency does not induce iron overload in mice (D. R. Campagna, P. J. Schmidt, and M.D.F., unpublished observations, January 2011). In contrast, Alk2 and Alk3 are abundantly expressed in hepatocytes. 21 To identify the type I BMP receptor required for th...

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“…The collagen "gel sandwich" configuration is a popular method for maintaining long-term hepatocyte functions. [251][252][253][254][255][256][257][258][259] Nonetheless, the successful development of cell-based artificial liver devices requires long-term, stable hepatocytic function in a perfusable environment and efficient transport of nutrients and waste within the device.…”

Section: Vf Liver Cell Biology On a Chipmentioning

confidence: 99%

Biology on a Chip: Microfabrication for Studying the Behavior of Cultured Cells

Tourovskaia

Folch

2003

Crit Rev Biomed Eng

173

140

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The ability to culture cells in vitro has revolutionized hypothesis testing in basic cell and molecular biology research and has become a standard methodology in drug screening and toxicology assays. However, the traditional cell culture methodology-consisting essentially of the immersion of a large population of cells in a homogeneous fluid medium-has become increasingly limiting, both from a fundamental point of view (cells in vivo are surrounded by complex spatiotemporal microenvironments) and from a practical perspective (scaling up the number of fluid handling steps and cell manipulations for high-throughput studies in vitro is prohibitively expensive). Micro fabrication technologies have enabled researchers to design, with micrometer control, the biochemical composition and topology of the substrate, the medium composition, as well as the type of neighboring cells surrounding the microenvironment of the cell. In addition, microtechnology is conceptually well suited for the development of fast, low-cost in vitro systems that allow for high-throughput culturing and analysis of cells under large numbers of conditions. Here we review a variety of applications of microfabrication in cell culture studies, with an emphasis on the biology of various cell types.

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Proline‐mediated enhancement of hepatocyte function in a collagen gel sandwich culture configuration

Cited by 46 publications

References 10 publications

Alginate‐PLL microencapsulation: Effect on the differentiation of embryonic stem cells into hepatocytes

Alginate‐PLL microencapsulation: Effect on the differentiation of embryonic stem cells into hepatocytes

Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice

Biology on a Chip: Microfabrication for Studying the Behavior of Cultured Cells

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