Science1 publisher2 min readPublished
High glucose drove inflammation in human kidney organoids that have no immune cells
In Stem Cell Reports, a team led by Benjamin Freedman reports that stem-cell-derived kidney organoids, which contain no immune cells and no blood vessels, shed podocytes in high-glucose media, and that blocking MIF or TNF-alpha protected them. The pattern resembles what patient biopsies show.
The Scientist · Science desk
What happened
- Freedman's team grew human kidney organoids in media at different glucose concentrations; the lower-glucose cultures stayed largely intact, while higher glucose brought progressive morphological deterioration.
- Podocytes and tubular epithelial cells came away from the main organoid body, a pattern the authors say resembles changes reported in kidney biopsies and urine samples from patients with diabetic kidney disease.
- Single-cell RNA sequencing put MIF at the top of the upregulated genes in the complete dataset, in the epithelial cluster and in the podocyte subcluster.
- Inhibiting MIF with ISO-1 or TNF-alpha with etanercept protected the organoids from podocyte injury under high glucose.
- The paper, "Elevated glucose in kidney organoids induces tissue-intrinsic inflammation driving epithelial detachment," was published in Stem Cell Reports.
Compiled by The ScientistSomething wrong?How this is made
Why it matters
- capability A dish with no immune cells and no vasculature lets a compound's effect on podocyte detachment be read without immune infiltration in the way. Animal models cannot isolate that test.
- decision A program picking a target gets three candidates sitting in the epithelium, and choosing among MIF, TNF-alpha and MEK inhibition has to be settled in preclinical work.
- constraint Since injury needed relatively high glucose without added TNF-alpha, the experiment cannot establish that the same signaling switches on at the blood sugars patients actually run.
Live/dead and lactate dehydrogenase assays argued against overt cytotoxicity in the high-glucose organoids [7], so the detachment is not explained by cells dying where they sat. Cells that come away alive make the phenotype comparable to a patient sample, where podocytes turn up in urine [8].
Several pathway-level changes, TNF-alpha/NF-kB signaling among them, overlapped with transcriptomic data from human diabetic kidney disease biopsies [11]. That overlap connects a dish result to patient tissue. Blocking the pathway separates a driver from a marker, and here MAPK inhibitors also partially rescued podocyte morphology [14]. "Thus, our scRNA-seq analysis suggested that high glucose levels promote TNF-alpha and MIF expression, driving inflammation and podocyte injury," the authors wrote [12].
"High sugar causes inflammation in these organoids even though they lack an immune system," said Freedman, who led the work at the University of Washington and the University of Miami [15][2]. "This was unexpected and gives us a new way to think about how diabetes can affect kidneys and other organs" [16].
The organoids are differentiated from pluripotent stem cells in stages [4] and have neither functional vasculature nor immune cells [18], so an inflammatory program showing up in epithelium came from the epithelium. The missing immune system also bounds the claim. The model cannot apportion the inflammation in a patient's kidney between resident tubular cells and immune cells arriving through vessels the organoids do not have.
There is a dose caveat as well. The authors report that the model required relatively high glucose to induce injury in the absence of TNF-alpha [17]. The published account describes the conditions only as lower and higher glucose, without giving the concentrations [6]. On what to do with the three targets, the authors wrote: "While our findings suggest that inhibitors of MIF, TNF-alpha, or MEK can be used to intervene in this process, careful consideration and preclinical studies are needed to determine which of these treatment strategies is likely to be most effective" [19].
About 40% of people with diabetes develop diabetic kidney disease, which can progress to kidney failure [20]. Few existing drugs do anything about the cellular damage inside the kidney; they control blood sugar and blood pressure [21].
What to watch
- A vascularized or immune-reconstituted version of the same organoid, which would test whether epithelium-derived signaling still accounts for the detachment.
- Animal work comparing MIF, TNF-alpha and MEK inhibition head to head on podocyte loss.
- Whether MIF turns up in patient urine or biopsy datasets as a measurable readout of active podocyte detachment.