iPS-technology and patient specific disease models

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The development and application of iPSC technology promises to revolutionize our understanding of disease mechanisms and improve the availability of treatment options. The ability to generate patient specific iPSC allows for the development of cell-based disease modeling where it has previously been extremely difficult to obtain sufficient amounts of the relevant human cell types to study such as cardiomyocytes, endothelial (ECs) and vascular smooth muscle cells (VSMCs). Further, this technology enables the investigation of mechanisms underlying cardiovascular diseases. We have to-date successfully generated a human iPSC biobank with several samples derived from healthy volunteers and patients carrying genetic defects for conditions such as ACDC, HIES (Jobs syndrome), SAVI, CADASIL, DADA2, ORAS, Turner Syndrome and Degos. The majority of iPSC lines have also been extensively characterized to exhibit the potential of unlimited self-renewal as well as the ability to differentiate into three germ layers. Additionally, we have established novel differentiation protocols with efficient, stage-wise, chemically-defined strategies for short-term induction of mesoderm lineage cells (ECs, MSCs, VSMCs, Hematopoietic lineage cells as well as the formation of blood vessel organoids using these cells). This approach has proven critical in increasing our understanding of the disease pathophysiology as well as allowed for testing of drugs/small molecules as potential novel therapeutic strategies or cell replacement therapy. Using these technologies with ACDC, we have demonstrated a compensatory upregulation of TNAP leading to an insufficient production of adenosine and a marked decrease in PPi, causing the vascular calcifications in ACDC samples from patients in vitro. In vivo, we also identified an inhibitory pathway downstream of the A2B adenosine receptor signaling pathway and several therapeutic drug targets, with etidronate being the most clinically viable candidate. On the other hand, when focusing on the underlying mechanisms of AD-HIES that is caused by loss-of-function mutations in signal transducer and activator of transcription 3 (STAT3), we were able to identify that STAT3 plays a critical role in reprogramming of somatic cells towards iPSCs through activation of Nanog. We alsodeveloped a teratoma model (murine) system with iPSC to explore pharmacological targets for treatment of AD-HIES. The research accomplished with these iPSC lines and their derivatives has led to a large volume of publications in Nature, Stem Cell Research, and Chemical Research in Toxicology over the last year. We plan to continue to apply these strategies to study the genetic cause and disease mechanisms with on-going research for DADA2, ORAS, Turner Syndrome and Degos as well as for other rare conditions with vascular phenotype that may have unclear genetic cause or pathomechanisms.