In Vitro Disease Modeling of Hermansky-Pudlak Syndrome Type 2 Using Human Induced Pluripotent Stem Cell-Derived Alveolar Organoids

Abstract

SummaryIt has been challenging to generate in vitro models of alveolar lung diseases, as the stable culture of alveolar type 2 (AT2) cells has been difficult. Methods of generating and expanding AT2 cells derived from induced pluripotent stem cells (iPSCs) have been established and are expected to be applicable to disease modeling. Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by dysfunction of lysosome-related organelles, such as lamellar bodies (LBs), in AT2 cells. From an HPS type 2 (HPS2) patient, we established disease-specific iPSCs (HPS2-iPSCs) and their gene-corrected counterparts. By live cell imaging, the LB dynamics were visualized and altered distribution, enlargement, and impaired secretion of LBs were demonstrated in HPS2-iPSC-derived AT2 cells. These findings provide insight into the AT2 dysfunction in HPS patients and support the potential use of human iPSC-derived AT2 cells for future research on alveolar lung diseases.

The Cellular and Physiological Basis for Lung Repair and Regeneration: Past, Present, and Future

“…However, a drawback of reporter lines is that this strategy is unlikely to be approved for the purification of human cells for clinical therapies. A second solution is the use of surface markers to enrich for lung endoderm progenitors such as carboxypeptidase M or CD47 hi CD26 lo cells (Gotoh et al, 2014;Hawkins et al, 2017;Korogi et al, 2019).…”

“…Further studies revealed an essential role for IL11 in the fibrotic process, suggesting that IL11 is a potential therapeutic target in this intractable disease (Strikoudis et al, 2019). Additional work using AT2 cells generated from patient-specific iPSCs profiled the AT2 cell dysfunction that results from HPS1 mutations (Korogi et al, 2019).…”

Regulation of JAM2 Expression in the Lungs of Streptozotocin-Induced Diabetic Mice and Human Pluripotent Stem Cell-Derived Alveolar Organoids

“…Thus, the need for a more accurate model system has moved the field towards developing 3D organoids from hPSCs, which are able to overcome the limited accessibility to primary normal human and diabetic lung tissues and provide a more faithful representation of native lung tissue [37]. In the lungs, several types of organoids that represent different respiratory compartments such as the proximal and distal airways have been successfully generated from hPSCs and already proven to be a great platform for the modeling of human lung development and pulmonary fibrosis [38][39][40][41]. However, no studies have been conducted to investigate the effects of hyperglycemic conditions on gene expression using hPSC-derived AO.…”

Understanding Human Lung Development through In Vitro Model Systems

“…To circumvent this limitation, several groups have developed methods to differentiate hPSCs into progenitors of the lung epithelium, [ 33 , 34 , 36 , 52 , 63 , 66 ] which can then give rise to alveolar cell types, partially recapitulating the development of the lung epithelium during sacculation and alveologenesis. Methods also exist to generate more purified populations of alveolar cells called alveolospheres, [ 22 , 34 , 101 , 102 , 130 ] which have already proven useful for modeling congenital disease of the alveoli [ 131 , 132 ] and alveolar injury. [ 133 ] These methods, although state-of-the-art, provide an incomplete picture of sacculation and alveolar development in humans because they either lack mesenchyme, [ 63 , 66 , 101 ] require exogenous mesenchyme for alveolar differentiation, [ 34 , 102 ] generate immature alveolar cells stochastically, [ 33 , 36 , 52 , 63 , 66 ] or give rise to ATII cells only.…”