Hepatocyte‐like cells generated by direct reprogramming from murine somatic cells can repopulate decellularized livers

Chen, Chen; Plá-Palacín, Iris; Baptista, Pedro M.; Shang, Peng; Oosterhoff, Loes A.; Wolferen, Monique E. van; Penning, Louis C.; Geijsen, Niels; Spee, Bart

doi:10.1002/bit.26784

Cited by 14 publications

(13 citation statements)

References 32 publications

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“…Studies investigating whether this approach is feasible are lacking. Several studies have successfully achieved reendothelialization (with or without coating the remaining ECM) and parenchymatous recellularization of liver scaffolds in vitro [8,20,64,73,112,113,[116][117][118][119][120][121][122][123]. Various cell types, such as hepatocytes (e.g.…”

Section: Livermentioning

confidence: 99%

Strategies based on organ decellularization and recellularization

et al. 2019

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Summary Transplantation is the only curative treatment option available for patients suffering from end‐stage organ failure, improving their quality of life and long‐term survival. However, because of organ scarcity, only a small number of these patients actually benefit from transplantation. Alternative treatment options are needed to address this problem. The technique of whole‐organ decellularization and recellularization has attracted increasing attention in the last decade. Decellularization includes the removal of all cellular components from an organ, while simultaneously preserving the micro and macro anatomy of the extracellular matrix. These bioscaffolds are subsequently repopulated with patient‐derived cells, thus constructing a personalized neo‐organ and ideally eliminating the need for immunosuppression. However, crucial problems have not yet been satisfyingly addressed and remain to be resolved, such as organ and cell sources. In this review, we focus on the actual state of organ de‐ and recellularization, as well as the problems and future challenges.

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Section: Livermentioning

confidence: 99%

Strategies based on organ decellularization and recellularization

et al. 2019

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“…Mechanistic mouse studies show that the activation of the Activin / Nodal – EOMES loop turns on the high levels of canonical TFs that control hepatogenesis in the mouse embryo. This includes Gata6 and Gata4 (Zhao et al, 2005), Foxa2 and Foxa1 (Lee et al, 2005), which have been implicated in pioneering chromatin remodeling in foregut precursors (Zaret and Carroll, 2011), and were utilized in the induction of hepatocyte transdifferentiation (Chen et al, 2018; Wamaitha et al, 2015). Moreover, Gata4 and Gata6 were shown to be functionally redundant in promoting the development of the liver, and together with Foxa2 they promote liver specification by inducing Hhex (Denson et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Single cell trajectory analysis of human pluripotent stem cells differentiating towards lung and hepatocyte progenitors

Ori

Ansari

Angelidis

et al. 2021

Preprint

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Understanding the development of human respiratory tissues is crucial for modeling and treating lung disorders. The molecular details for the specification of lung progenitors from human pluripotent stem cells (hPSCs) are unclear. Here, we use single cell RNA-sequencing with high temporal resolution along an optimized differentiation protocol to determine the transcriptional hierarchy of lung specification from human hPSCs and map out the underlying single cell trajectories. We show that Sonic hedgehog, TGF-β and Notch activation are required in an ISL1/NKX2-1 trajectory that gives rise to lung progenitors during the foregut endoderm stage. Induction of HHEX marks an alternative trajectory at the early definitive endoderm stage, which precedes the lung trajectory and generates a major hepatoblast population. Moreover, neither KDR+ nor mesendoderm progenitors are apparent intermediate states of lung and hepatic lineages. Our hierarchical multistep model predicts mechanisms leading to lung organogenesis, and creates a basis for studying early human lung development, as well as hPSC based disease and drug research.

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“…Furthermore, expandable through several scale-up cultivation protocols, iHeps can be used as a source for drug discovery and screening [10–12]. Chen and colleague demonstrated that iHeps repopulate a decellularized liver disc [16]. In this study, the decellularized liver provides an optimal microenvironment for in vitro maturation of iHeps.…”

Section: Introductionmentioning

confidence: 89%

Oct4 and Hnf4α-induced hepatic stem cells ameliorate chronic liver injury in liver fibrosis model

et al. 2019

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Direct conversion from fibroblasts to generate hepatocyte like-cells (iHeps) bypassing the pluripotent state has been described in previous reports as an attractive method acquiring hepatocytes for cell-based therapy. The limited proliferation of iHeps, however, has hampered it uses in cell-based therapy. Since hepatic stem cells (HepSCs) possess self-renewal and bipotency with the capacity to differentiate into both hepatocytes and cholangiocytes, they have therapeutic potential for treating liver disease. Here, we investigated the therapeutic effects of induced HepSCs (iHepSCs) on a carbon tetrachloride (CCl 4 )-induced liver fibrosis model. We demonstrate that Oct4 and Hnf4a are sufficient to convert fibroblasts into expandable iHepSCs. Hepatocyte-like cells derived from iHepSCs (iHepSC-HEPs) exhibit the typical morphology of hepatocytes and hepatic functions, including glycogen storage, low-density lipoprotein (LDL) uptake, Indocyanine green (ICG) detoxification, drug metabolism, urea production, and albumin secretion. iHepSCs-derived cholangiocyte-like cells (iHepSC-CLCs) expressed cholangiocyte-specific markers and formed cysts and tubule-like structures with apical-basal polarity and secretory function in three-dimensional culture condition. Furthermore, iHepSCs showed anti-inflammatory and anti-fibrotic effects in CCl 4 -induced liver fibrosis. This study demonstrates that Oct4 and Hnf4α -induced HepSCs show typical hepatic and biliary functionality in vitro . It also presents the therapeutic effect of iHepSCs in liver fibrosis. Therefore, directly converting iHepSCs from somatic cells may facilitate the development of patient-specific cell-based therapy for chronic liver damage.

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Hepatocyte‐like cells generated by direct reprogramming from murine somatic cells can repopulate decellularized livers

Cited by 14 publications

References 32 publications

Strategies based on organ decellularization and recellularization

Strategies based on organ decellularization and recellularization

Single cell trajectory analysis of human pluripotent stem cells differentiating towards lung and hepatocyte progenitors

Oct4 and Hnf4α-induced hepatic stem cells ameliorate chronic liver injury in liver fibrosis model

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