Asymmetric BMP4 signalling improves the realism of kidney organoids

Mills, Christopher G.; Lawrence, Melanie L.; Munro, David A. D.; Elhendawi, Mona; Mullins, John J.; Davies, Jamie A.

doi:10.1038/s41598-017-14809-8

Cited by 33 publications

(30 citation statements)

References 25 publications

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“…For instance, BMP4 is essential for mesoderm formation and patterning [46, 47]. Recently, BMP4 was shown to contribute to branching of the collecting duct in kidney organoid formation [48]. In accordance with this pathway activation in EL clones that maintain both epithelial phenotype and epithelial transcriptional signature, several BMP proteins (i.e.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of clonal human renal forming cells

Osnat

Rotem

Orit

et al. 2020

Preprint

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The adult kidney replaces its parenchyma in vivo in steady state and during regeneration by segment-specific clonal cell proliferation.To understand human adult kidney clonal cell growth, we derived tissue from human nephrectomies and performed limiting dilution to establish genuine clonal cultures from one single cell.Clonal efficiency of the human kidney was x%. Remarkably, a single renal cell could give rise to up to 3.3*10(6) cells. Phenotypically, two types of clonal cultures were apparent; a stably proliferating cuboidal epithelial-like appearing (EL) and a rapidly proliferating fibroblast-like appearing (FL). RNA sequencing of all clonal cultures separated FL from EL cultures according to proximal-distal/collecting renal epithelial tubular identity, respectively. Moreover, distinct molecular features in respect to cellcycle, epithelial-mesenchymal transition, oxidative phosphorylation, BMP signaling pathway and cell surface markers were observed for each clone type. Surprisingly, clonal expansion (>3 months) was sustained in EL clones harboring markers of mature kidney epithelia (high CD24, CDH1, EpCAM, EMA) in contrast to dedifferentiated FL clones (high NCAM1, serpine1), which showed fast lineage amplification and exhausted in a few weeks. Thus, the human adult kidney harbors progenitor cell function in which segment identity and the level of epithelial differentiation dictate clonal characteristics.2 4 . Liu, J., et al., Loss of SETD2 Induces a Metabolic Switch in Renal Cell Carcinoma Cell Lines toward Enhanced Oxidative Phosphorylation . J Proteome Res, 2019. 18(1): p. 331-340.2 5 . , L., et al., Clear Cell Renal Cell Carcinoma is linked to Epithelial-to-Mesenchymal Transition and to Fibrosis. Physiol Rep, 2017. 5(11.( 2 6 . Sanchez, D.J. and M.C. Simon, Genetic and metabolic hallmarks of clear cell renal cell carcinoma. Biochim Biophys Acta Rev Cancer, 2018. 1870(1): p. 23-31. Landolt2 7 .Buzhor, E., et al., Cell-based therapy approaches: the hope for incurable diseases. Regen Med, 2014. 9(5): p. 649-72. 2 8 . Chuang, C.H., et al., Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat Med, 2017. 23(3): p. 291-300.

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Section: Discussionmentioning

confidence: 99%

Molecular characterization of clonal human renal forming cells

Osnat

Rotem

Orit

et al. 2020

Preprint

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“…Meanwhile, several research groups are studying the molecular cues that direct the development of the ureter and urinary bladder. For example bone morphogenetic protein 4-soaked beads placed near an organoid broke the symmetry of the system, causing a nearby collecting duct to develop into an ureter-like 'trunk', while away from the bead collecting duct branching and nephron formation were not disturbed [100]. On a side note, considerable variations between experiments, clones, as well as research groups, have been reported, which could partly be related to the several protocols currently used to obtain kidney organoids [101].…”

Section: Kidney Organoidsmentioning

confidence: 99%

Bioengineering strategies for nephrologists: kidney was not built in a day

Peired

Mazzinghi

Chiara

et al. 2020

Expert Opinion on Biological Therapy

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Introduction: The number of patients with end-stage kidney disease is increasing worldwide, creating an unprecedented organ shortage. The kidney is a highly complex structure performing many crucial functions. Dialysis replaces filtration but not all other kidney functions and transplant is limited by kidney availability. Numerous innovative ways are being explored to obtain new kidneys for disease modeling and potentially replace lost kidney functions. Areas covered: In this review, we will go through the different approaches that have been developed over the years to build kidneys. We will first present the current advances in xenotransplantation and generation of interspecies chimeras. Next, we will examine the attempts to create bioengineered kidneys with hemodialysis-derived implantable devices and decellularized organs. Finally, we will examine how organoids and microfluidic devices could answer important pathophysiological questions and model the path toward creating in vitro functional organs, for example through 3D bioprinting. Expert opinion: While all the aforementioned approaches to create new kidneys are promising, their translation into clinical practice seems a long way off, except xenotransplantation. Nonetheless, these novel technologies already consent disease modeling and drug testing at 3D level. We will review the stages of progress toward patient therapy and advantages/drawbacks of the various strategies.

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“…Moreover, this system has been applied to construct UB-like tubules from healthy individuals and a patient with a PAX2 mutation and to study normal UB developmental processes and patient-specific defects. A different approach has shown that the local application of signals (e.g., bead-releasing morphogenetic factors) ( Mills et al, 2017 ) or technical manipulations of engineered tissues (e.g., assembly of previously engineered organ component tissues) ( Taguchi and Nishinakamura, 2017 ) could be used to add key missing information to self-organizing tissue to produce more anatomically realistic organoids.…”

Section: Key Technical Milestones To Be Achievedmentioning

confidence: 99%

Kidney Organoids as Disease Models: Strengths, Weaknesses and Perspectives

2020

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Chronic kidney disease is a major global health problem, as it affects 10% of the global population and kills millions of patients every year. It is therefore of the utmost importance to develop models that can help us to understand the pathogenesis of CKD and improve our therapeutic strategies. The discovery of human induced pluripotent stem cells (hiPSCs) and, more recently, the development of methods for the generation of 3D organoids, have opened the way for modeling human kidney development and disease in vitro , and testing new drugs directly on human tissue. In this review we will discuss the most recent advances in the field of kidney organoids for modeling disease, as well as the prospective applications of these models for drug screening. We will also emphasize the impact of CRISPR/cas9 genome engineering on the field, point out the current limitations of the existing organoid technologies, and discuss a set of technical developments that may help to overcome limitations and facilitate the incorporation of these exciting tools into basic biomedical research.

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Asymmetric BMP4 signalling improves the realism of kidney organoids

Cited by 33 publications

References 25 publications

Molecular characterization of clonal human renal forming cells

Molecular characterization of clonal human renal forming cells

Bioengineering strategies for nephrologists: kidney was not built in a day

Kidney Organoids as Disease Models: Strengths, Weaknesses and Perspectives

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