Harnessing developmental plasticity to pattern kidney organoids

Bhattacharya, Rohan; Bonner, Makenzie G.; Musah, Samira

doi:10.1016/j.stem.2021.03.009

Cited by 7 publications

(7 citation statements)

References 9 publications

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“…Because stem cells can self-renew indefinitely and differentiate into almost any cell type when provided appropriate signals, they serve as virtually unlimited supply of organ-specific cells including podocytes ( Musah et al, 2017 ). Derivatives of human pluripotent stem cells have also been used for disease modelling and drug discovery assays ( Ilic and Ogilvie, 2017 ; Bhattacharya et al, 2021 ; Okafor et al, 2021 ; Kalejaiye et al, 2022 ). We previously developed a method to directly differentiate human iPS cells into cells that exhibit morphological, molecular, and functional characteristics of the mature human kidney glomerular podocytes ( Musah et al, 2017 ; Musah et al, 2018 ; Burt et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Employ BSG/CD147 and ACE2 Receptors to Directly Infect Human Induced Pluripotent Stem Cell-Derived Kidney Podocytes

Kalejaiye

Bhattacharya

Burt

et al. 2022

Front. Cell Dev. Biol.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the Coronavirus disease 2019 (COVID-19), which has resulted in over 5.9 million deaths worldwide. While cells in the respiratory system are the initial target of SARS-CoV-2, there is mounting evidence that COVID-19 is a multi-organ disease. Still, the direct affinity of SARS-CoV-2 for cells in other organs such as the kidneys, which are often targeted in severe COVID-19, remains poorly understood. We employed a human induced pluripotent stem (iPS) cell-derived model to investigate the affinity of SARS-CoV-2 for kidney glomerular podocytes, and examined the expression of host factors for binding and processing of the virus. We studied cellular uptake of the live SARS-CoV-2 virus as well as a pseudotyped virus. Infection of podocytes with live SARS-CoV-2 or spike-pseudotyped lentiviral particles revealed cellular uptake even at low multiplicity of infection (MOI) of 0.01. We found that direct infection of human iPS cell-derived podocytes by SARS-CoV-2 virus can cause cell death and podocyte foot process retraction, a hallmark of podocytopathies and progressive glomerular diseases including collapsing glomerulopathy observed in patients with severe COVID-19 disease. We identified BSG/CD147 and ACE2 receptors as key mediators of spike binding activity in human iPS cell-derived podocytes. These results show that SARS-CoV-2 can infect kidney glomerular podocytes in vitro via multiple binding interactions and partners, which may underlie the high affinity of SARS-CoV-2 for kidney tissues. This stem cell-derived model is potentially useful for kidney-specific antiviral drug screening and mechanistic studies of COVID-19 organotropism.

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Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Employ BSG/CD147 and ACE2 Receptors to Directly Infect Human Induced Pluripotent Stem Cell-Derived Kidney Podocytes

Kalejaiye

Bhattacharya

Burt

et al. 2022

Front. Cell Dev. Biol.

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“…Additionally, heterogeneity in disease phenotypes and varied response to drugs in different patients emphasize the need for more personalized disease modeling approaches. Miniaturized multicellular static culture models (i.e., kidney organoids, transwells, and conventional 2D systems) are useful for understanding nephrogenesis, but these stochastic models often represent the developmental state of first- or second-trimester kidneys, thus lacking the structure and functional characteristics of the specialized kidneys (e.g., vascularization), as well as mechanical factors that promote maturation and in vivo-like phenotypes [ 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

A Personalized Glomerulus Chip Engineered from Stem Cell-Derived Epithelium and Vascular Endothelium

et al. 2021

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Progress in understanding kidney disease mechanisms and the development of targeted therapeutics have been limited by the lack of functional in vitro models that can closely recapitulate human physiological responses. Organ Chip (or organ-on-a-chip) microfluidic devices provide unique opportunities to overcome some of these challenges given their ability to model the structure and function of tissues and organs in vitro. Previously established organ chip models typically consist of heterogenous cell populations sourced from multiple donors, limiting their applications in patient-specific disease modeling and personalized medicine. In this study, we engineered a personalized glomerulus chip system reconstituted from human induced pluripotent stem (iPS) cell-derived vascular endothelial cells (ECs) and podocytes from a single patient. Our stem cell-derived kidney glomerulus chip successfully mimics the structure and some essential functions of the glomerular filtration barrier. We further modeled glomerular injury in our tissue chips by administering a clinically relevant dose of the chemotherapy drug Adriamycin. The drug disrupts the structural integrity of the endothelium and the podocyte tissue layers, leading to significant albuminuria as observed in patients with glomerulopathies. We anticipate that the personalized glomerulus chip model established in this report could help advance future studies of kidney disease mechanisms and the discovery of personalized therapies. Given the remarkable ability of human iPS cells to differentiate into almost any cell type, this work also provides a blueprint for the establishment of more personalized organ chip and ‘body-on-a-chip’ models in the future.

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“…During kidney organogenesis, cells of the primitive streak give rise to the mesoderm, which then differentiates to form the intermediate mesoderm (IM). The medio-posterior IM produces the ureteric epithelium and the metanephric mesenchyme, which are further specialized into the collecting ducts and nephron, respectively [19][20][21][22][23]. Studying tissue and organ biology in mammals can be challenging due to ethical concerns and limited access to samples.…”

Section: Transforming Stem Cells Into Kidney Organoidsmentioning

confidence: 99%

“…However, recent advances in stem cell biology have afforded extraordinary opportunities to model kidney development and disease using 2D [15,24] or 3D [17,25] cell culture systems. When provided appropriate biochemical and biophysical cues, stem cells can proliferate and form organoids that recapitulate some of the multicellular composition and early stages of tissue development [19,25]. These features make kidney organoids important models of organ development and disease, with implications for fundamental studies of human biology, drug discovery, and regenerative medicine.…”

Section: Transforming Stem Cells Into Kidney Organoidsmentioning

confidence: 99%

Translating Organoids into Artificial Kidneys

2022

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Purpose of Review Kidney disease affects more than 13% of the world population, and current treatment options are limited to dialysis and organ transplantation. The generation of kidney organoids from human-induced pluripotent stem (hiPS) cells could be harnessed to engineer artificial organs and help overcome the challenges associated with the limited supply of transplantable kidneys. The purpose of this article is to review the progress in kidney organoid generation and transplantation and highlight some existing challenges in the field. We also examined possible improvements that could help realize the potential of organoids as artificial organs or alternatives for kidney transplantation therapy. Recent Findings Organoids are useful for understanding the mechanisms of kidney development, and they provide robust platforms for drug screening, disease modeling, and generation of tissues for organ replacement therapies. Efforts to design organoids rely on the ability of cells to self-assemble and pattern themselves into recognizable tissues. While existing protocols for generating organoids result in multicellular structures reminiscent of the developing kidney, many do not yet fully recapitulate the complex cellular composition, structure, and functions of the intact kidney. Recent advances toward achieving these goals include identifying cell culture conditions that produce organoids with improved vasculature and cell maturation and functional states. Still, additional improvements are needed to enhance tissue patterning, specialization, and function, and avoid tumorigenicity after transplantation. Summary This report focuses on kidney organoid studies, advancements and limitations, and future directions for improvements towards transplantation.

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Harnessing developmental plasticity to pattern kidney organoids

Cited by 7 publications

References 9 publications

SARS-CoV-2 Employ BSG/CD147 and ACE2 Receptors to Directly Infect Human Induced Pluripotent Stem Cell-Derived Kidney Podocytes

SARS-CoV-2 Employ BSG/CD147 and ACE2 Receptors to Directly Infect Human Induced Pluripotent Stem Cell-Derived Kidney Podocytes

A Personalized Glomerulus Chip Engineered from Stem Cell-Derived Epithelium and Vascular Endothelium

Translating Organoids into Artificial Kidneys

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