Search

Surfactant protein B (SFTPB) deficiency is a fatal disease affecting newborn infants. Surfactant is produced by alveolar type II cells which can be differentiated in vitro from patient specific induced pluripotent stem cell (iPSC)-derived lung organoids. Here we show the differentiation of patient specific iPSCs derived from a patient with SFTPB deficiency into lung organoids with mesenchymal and epithelial cell populations from both the proximal and distal portions of the human lung. We alter the deficiency by infecting the SFTPB deficient iPSCs with a lentivirus carrying the wild type SFTPB gene. After differentiating the mutant and corrected cells into lung organoids, we show expression of SFTPB mRNA during endodermal and organoid differentiation but the protein product only after organoid differentiation. We also show the presence of normal lamellar bodies and the secretion of surfactant into the cell culture medium in the organoids of lentiviral infected cells. These findings suggest that a lethal lung disease can be targeted and corrected in a human lung organoid model in vitro.

Throughout much of human and medical history the brain has been a black box opaque to scientific investigation for a myriad of reasons ranging from societal to logistical barriers. Compounding this opacity, the biological effects of ecologically sourced medicines that early cultures, and many current societies, prescribed were inherently elusive due to technological hurdles. However, in modern medicine and science, these challenges are now surmountable. Healthy and diseased human patient neurons are now more accessible, as noninvasively collected somatic cells, such as skin cells, can be reprogrammed into induced pluripotent stem cells (iPSCs) and then differentiated into neurons in vitro. Due to this contemporary ability to grow patient neurons in a dish, in conjunction with tractable animal models, functional agents can now be deployed to pry open the black box and gain insight into the construction of the brain and the pathophysiology of disease. This chapter will use case studies of peer-reviewed and published research to demonstrate the explanatory power of functional agents that serve as ‘molecular can openers’, such as in the case of the functional agent lithium in the context of bipolar disorder. This chapter will also consider the value iPSCs provide to research and development and offer thoughts on the business and translational aspects of this technology as well as share contemplations on the future of this field. This chapter aims to depict how collaboration between basic science laboratories, clinical research institutions, biotechnology businesses, regulatory apparatuses and healthcare providers can not only improve health and profit outcomes but also improve performance along the innovation S-curve.

The pathogenesis of bipolar disorder (BPD) is unknown. Using human-induced pluripotent stem cells (hiPSCs) to unravel pathological mechanisms in polygenic diseases is challenging, with few successful studies to date. However, hiPSCs from BPD patients responsive to lithium have offered unique opportunities to discern lithium’s mechanism of action and hence gain insight into BPD pathology. By profiling the proteomics of BPD–hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). The “set point” for the ratio of pCRMP2:CRMP2 is elevated uniquely in hiPSC-derived neurons from lithium responsive (Li-R) BPD patients, but not other psychiatric and neurological disorders. Utilizing neurons differentiated from human patient stem cells as an in vitro platform, we were able to elucidate the mechanism driving the pathogenesis and pathophysiology of lithium-responsive BPD, heretofore unknown. Importantly, the findings in culture were validated in human postmortem material as well as in animal models of BPD behavior. These data suggest that the “lithium response pathway” in BPD governs CRMP2’s phosphorylation, which regulates cytoskeletal organization, particularly in dendritic spines, leading to modulated neural networks that may underlie Li-R BPD pathogenesis. This chapter reviews the methodology of leveraging a functional agent, lithium, to identify unknown pathophysiological pathways with hiPSCs and how to translate this disease modeling approach to other neurological disorders.