Differentiation of Hepatocytes from Pluripotent Stem Cells

Mallanna, Sunil K.; Duncan, Stephen A.

doi:10.1002/9780470151808.sc01g04s26

Cited by 102 publications

(105 citation statements)

References 29 publications

(44 reference statements)

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“…S5) are important in controlling the quality and purity of hiPSC-HPCs for the bioprinting process and thus the functional performance of the model. Moreover, future study on the mesenchymal to epithelial transition process, which is omitted by many current hepatic differentiation protocols (7,8,12,13), can be carried out to understand, in depth, the differentiation from HPCs to more mature hepatic epithelia. When assessing the albumin production levels of hiPSC-HPCs and HLCs following GelMA encapsulation, the higher magnitude and more sustained level of albumin produced following the peak by HPCs supported their potential to be better candidates for the 3D hydrogel encapsulation.…”

Section: Discussionmentioning

confidence: 99%

“…hiPSCs generated from fibroblasts were induced to differentiate into hepatic lineage by a fourstage differentiation protocol modified from previous published methods ( Fig. S4) (8). After differentiation initiation, cells at each of the four major stages, i.e., definitive endoderm, hepatic endoderm, hepatic progenitor, and further hepatic maturation, expressed stagespecific markers as confirmed by immunofluorescent staining ( Fig.…”

Section: D Hydrogel Encapsulation At Hepatic Progenitor Stage Demonsmentioning

confidence: 99%

“…2B) (13,29,30). Following hepatic lineage specification, cells entered hepatic progenitor stage, i.e., became HPCs after 12-14 d of differentiation, which further matured into HLCs after 17-19 d of differentiation (8,30).…”

Section: D Hydrogel Encapsulation At Hepatic Progenitor Stage Demonsmentioning

confidence: 99%

“…Many groups have reported monolayer differentiation of hiPSCs into hepatocyte-like cells (HLCs) and their ability to metabolize drugs (7)(8)(9). Nevertheless, hiPSC-derived HLCs are still considered immature in terms of many liver-specific gene expressions, functions, and cytochrome P450 (CYP) enzyme activities (7,9).…”

mentioning

confidence: 99%

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Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting

Zhu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

726

661

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The functional maturation and preservation of hepatic cells derived from human induced pluripotent stem cells (hiPSCs) are essential to personalized in vitro drug screening and disease study. Major liver functions are tightly linked to the 3D assembly of hepatocytes, with the supporting cell types from both endodermal and mesodermal origins in a hexagonal lobule unit. Although there are many reports on functional 2D cell differentiation, few studies have demonstrated the in vitro maturation of hiPSC-derived hepatic progenitor cells (hiPSC-HPCs) in a 3D environment that depicts the physiologically relevant cell combination and microarchitecture. The application of rapid, digital 3D bioprinting to tissue engineering has allowed 3D patterning of multiple cell types in a predefined biomimetic manner. Here we present a 3D hydrogel-based triculture model that embeds hiPSC-HPCs with human umbilical vein endothelial cells and adiposederived stem cells in a microscale hexagonal architecture. In comparison with 2D monolayer culture and a 3D HPC-only model, our 3D triculture model shows both phenotypic and functional enhancements in the hiPSC-HPCs over weeks of in vitro culture. Specifically, we find improved morphological organization, higher liver-specific gene expression levels, increased metabolic product secretion, and enhanced cytochrome P450 induction. The application of bioprinting technology in tissue engineering enables the development of a 3D biomimetic liver model that recapitulates the native liver module architecture and could be used for various applications such as early drug screening and disease modeling.3D bioprinting | in vitro hepatic model | iPSC | tissue engineering | biomaterials T he liver plays a critical role in the synthesis of important proteins and the metabolism of xenobiotic; the failure of these functions is closely related to disease development and drug-induced toxicity (1). For these reasons, in vitro liver models have been extensively developed to serve as platforms for pathophysiological studies and as alternatives to animal models in drug screening and hepatotoxicity prediction (2-4). Human primary hepatocytes, considered one of the most mature liver cell sources, lose many liver-specific functions rapidly when cultured in vitro due to the great discrepancies between the native and culture environments (5, 6). In addition, the practical difficulties in obtaining liver biopsy samples from every patient further hinder their use in personalized liver models. Consequently, hepatocytes derived from human induced pluripotent stem cells (hiPSCs), with the potential to be patient specific and easily accessible, have been widely acknowledged as the most promising cell source for developing personalized human hepatic models (4, 7).Many groups have reported monolayer differentiation of hiPSCs into hepatocyte-like cells (HLCs) and their ability to metabolize drugs (7-9). Nevertheless, hiPSC-derived HLCs are still considered immature in terms of many liver-specific gene expressions, functions, and...

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Section: Discussionmentioning

confidence: 99%

Section: D Hydrogel Encapsulation At Hepatic Progenitor Stage Demonsmentioning

confidence: 99%

Section: D Hydrogel Encapsulation At Hepatic Progenitor Stage Demonsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting

Zhu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

726

661

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“…While dual SMAD inhibition is sufficient to induce rapid and complete neural conversion of human ESCs and iPSCs 110, there are limitations to efficiently differentiate PSCs to other cell types, such as cardiomyocytes 111, kidney cells 112, retinal pigment epithelium 113, or hepatocytes 114. In particular, the differentiated cells produced are largely immature, and resemble the fetal stages of development 111, 114, which hampers their ability to engraft and function in coordination with other cells of the tissue. In order to overcome these problems and provide more insights into cell‐fate commitment, computational modeling of single‐cell data will be essential for uncovering the mechanisms regulating self‐renewal, and triggering differentiation from a systems‐level perspective.…”

Section: Modeling Heterogeneity In the Pluripotent State Will Be Essementioning

confidence: 99%

Modeling heterogeneity in the pluripotent state: A promising strategy for improving the efficiency and fidelity of stem cell differentiation

Angarica

Sol

2016

BioEssays

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Pluripotency can be considered a functional characteristic of pluripotent stem cells (PSCs) populations and their niches, rather than a property of individual cells. In this view, individual cells within the population independently adopt a variety of different expression states, maintained by different signaling, transcriptional, and epigenetics regulatory networks. In this review, we propose that generation of integrative network models from single cell data will be essential for getting a better understanding of the regulation of self‐renewal and differentiation. In particular, we suggest that the identification of network stability determinants in these integrative models will provide important insights into the mechanisms mediating the transduction of signals from the niche, and how these signals can trigger differentiation. In this regard, the differential use of these stability determinants in subpopulation‐specific regulatory networks would mediate differentiation into different cell fates. We suggest that this approach could offer a promising avenue for the development of novel strategies for increasing the efficiency and fidelity of differentiation, which could have a strong impact on regenerative medicine.

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Natural and Synthetic Materials for Self‐Renewal, Long‐Term Maintenance, and Differentiation of Induced Pluripotent Stem Cells

Dzhoyashvili

Shen

Rochev

2015

Adv Healthcare Materials

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Induced pluripotent stem cells (iPSCs) have attracted considerable attention from the public, clinicians, and scientists since their discovery in 2006, and raised huge expectations for regenerative medicine. One of the distinctive features of iPSCs is their propensity to differentiate into the cells of three germ lines in vitro and in vivo. The human iPSCs can be used to study the mechanisms underlying a disease and to monitor the disease progression, for testing drugs in vitro, and for cell therapy, avoiding many ethical and immunologic concerns. This technology offers the potential to take an individual approach to each patient and allows a more accurate diagnosis and specific treatment. However, there are several obstacles that impede the use of iPSCs. The derivation of fully reprogrammed iPSCs is expensive, time-consuming, and demands meticulous attention to many details. The use of biomaterials could increase the efficacy and safety while decreasing the cost of tissue engineering. The choice of a substrate utilized for iPSC culture is also important because cell-substrate contacts influence cellular behavior such as self-renewal, expansion, and differentiation. This Progress Report aims to summarize the advantages and drawbacks of natural and synthetic biomaterials, and to evaluate their role for maintenance and differentiation of iPSCs.

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Differentiation of Hepatocytes from Pluripotent Stem Cells

Cited by 102 publications

References 29 publications

Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting

Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting

Modeling heterogeneity in the pluripotent state: A promising strategy for improving the efficiency and fidelity of stem cell differentiation

Natural and Synthetic Materials for Self‐Renewal, Long‐Term Maintenance, and Differentiation of Induced Pluripotent Stem Cells

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