Recapitulating human tissue damage, repair, and fibrosis with human pluripotent stem cell-derived organoids

Abstract

As new applications for human pluripotent stem cell‐derived organoids in drug screenings and tissue replacement therapies emerge, there is a need to examine the mechanisms of tissue injury and repair recently reported for various organoid models. In most cases, organoids contain the main cell types and tissues present in human organs, spatially arranged in a manner that largely resembles the architecture of the organ. Depending on the differentiation protocol used, variations may exist in cell type ratios relative to the organ of reference, and certain tissues, including some parenchymal components and the endothelium, might be poorly represented, or lacking altogether. Despite those caveats, recent studies have shown that organoid tissue injury recapitulates major events and histopathological features of damaged human tissues. In particular, major mechanisms of parenchyma cell damage and interstitial fibrosis can be reproduced with remarkable faithfulness. Although further validation remains to be done in order to establish the relevance of using organoid for either mechanistic studies or drug assays, this technology is becoming a promising tool for the study of human tissue homeostasis, injury, and repair.

The myofibroblast at a glance

“…A more-complex in vitro environment, with respect to production and interpretation, can be generated by using myofibroblast-derived ECM, either with cells still present or removed with detergents (Benny and Raghunath, 2017;Franco-Barraza et al, 2016). 'High-end' versions are organotypic cultures and stem cell-derived organoids with multiple levels of complexity and cell types involved (Moulin, 2013;Sobral-Reyes and Lemos, 2020;Sundarakrishnan et al, 2018). If human tissue is available for experimental studies, myofibroblast cultures can be established and studied on living-tissue slices that have been precision-cut with a vibratome, or by using ECM directly derived from decellularized organs (Clouzeau-Girard et al, 2006;Paish et al, 2019;Parker et al, 2014;Uhl et al, 2017).…”

Human reconstructed kidney models

“…Both pericyte-like PDGFRα+ cells and interstitial PDGFRβ+ fibroblasts have also been identified in the interstitium of human kidney organoids. Pericytes within the organoid are similar to pericytes observed in vivo and are present along the interstitial vessels and peritubular fibroblasts are immersed in the connective tissue coating the basal face of proximal tubules (Lemos et al 2018;Sobral-Reyes and Lemos 2020). The presence of these interstitial cell populations is further confirmed by single-cell RNA-seq analysis (Combes et al 2019).…”

“…Fibrosis progression was confirmed by the accumulation of myofibroblasts around the damaged proximal tubule of the organoid and the overaccumulation of collagen I (COL1A1), a component of the extracellular matrix. Increased gene expression of fibronectin I (FN1), COL1A1, and ACTA2, which have been evaluated to confirm the progression of fibrosis in human kidneys, was also observed (Lemos et al 2018;Sobral-Reyes and Lemos 2020). These results indicate that organoids can mimic fibrosis in the kidney, suggesting that organoids can be a very useful tool for overcoming fibrosis, which is a key issue in overcoming CKD.…”

Multilineage-Differentiating Stress-Enduring Cells: A Powerful Tool for Tissue Damage Repair

“…Today, there is an increasing need to replace or regenerate damaged tissue due to age-related and other degenerative diseases, tumors, trauma, and congenital defects [1]. Various tissue engineering methods including functional biomaterials, drug-eluting systems, and stem cell therapies have been used to enhance tissue regeneration [2][3][4].…”