A Multi-organoid, Multi-modality AI Model for Heterogeneity and Precision Medicine in Type 2 Diabetes (MOMENT)

National Center For Advancing Translational Sciences

Investigators

Abstract

Human PSCs have been shown to be able to be differentiated into many types of cells/organoids, which have been utilized to model various disease including type 2 diabetes (T2D). For example, Dr. Ron Kahn’s lab created a cellular model of human muscle insulin resistance by differentiating iPSCs from individuals with mutations in the insulin receptor into functional myotubes and showed their impaired response to insulin. In addition, they studied the interactions among insulin resistance, epigenetics, and donor sex in gene expression regulation of iPSC-derived myoblasts. The Chen and other groups, have applied hPSC-derived pancreatic β-like cells to study the effect of T2D-implicated genes, including NEUROG3, PDX1, GLIS3, ARX, GATA6, and SIX2, among others on β cell differentiation, function, and survival. Doege et al generated PCSK1 (PC1/3)-deficient hESC lines and investigated pro-opiomelanocortin (POMC) processing using hESC-differentiated hypothalamic neurons. Groeger et al co-cultured insulin-sensitive iPSC-derived hepatocytes with isogenic iPSC-derived pro-inflammatory macrophages and found that pro-inflammatory macrophages induce glucose output by preventing insulin from inhibiting gluconeogenesis and glycogenolysis and activating glycolysis. Our vision is to integrate hPSC-derived multi-organoids (in vitro) with a multi-modality AI model (in silico) to develop a combinatorial NAM model for studying T2D heterogeneity and precision medicine. iPSCs from 500 T2D patients have been generate, each with whole genome sequencing (WGS) data and corresponding clinical records. For the in vitro component, we will differentiate 96 iPSC lines, representing six subgroups based on partitioned diabetes polygenic risk scores, obesity-related insulin resistance, lipid metabolism dysregulation, beta-cell dysfunction, proinsulin processing deficiency, liver dysfunction, and non-T2D controls, with 8 male and 8 female lines per subgroup. These lines will be used to generate five major cellular populations/organoids that correspond to the primary target organs of ADA-recommended T2D drugs, including vascularized-immuno islet (VM-islet) organoids, hepatocytes (iHep), iMyo, kidney organoids, and hypothalamic neurons. These cells/organoids will be characterized for cellular identity, functionality, and drug response, with single-nucleus multiomics analysis applied to monitor transcriptional and epigenetic changes in the presence and absence of drug treatments. For the in silico component, multi-modality data—including functional analysis, sn-multiomics profiles, whole genome sequencing, and clinical records, will be used to train multi-modality AI models for T2D patient subgrouping and precision medicine approaches. The primary focus of SCTL scientists in the past year has been to utilize rigorous and efficient iPSC differentiation protocols for a variety of cell types relevant for both disease modeling and cell therapy applications, hypothalamic arcuate neurons (e.g., T2D), nociceptors (e.g., pain research), cortical neurons (e.g., Tay Sachs disease), astrocytes (e.g., free sialic acid storage disease), insulin-producing cells (e.g., type 1 diabetes), hepatocytes (e.g., liver failure), trophectoderm (e.g., placental development), cerebellar organoids (e.g., Friedreich’s ataxia), and dorsal root ganglion organoids (e.g., chemotherapy induced peripheral neuropathy). In FY25, our lab published six manuscripts. One manuscript demonstrates the effects of satellite glia on iPSC-derived sensory neuron differentiation and maturation. The second manuscript demonstrates the translational application of iPSC-derived hypothalamic arcuate neurons for the identification of environmental compounds that may trigger early female puberty. The third manuscript demonstrates a highly efficient protocol for the generation of iPSC-derived trophoblast. The fourth manuscript establishing a scalable differentiation platform for the generation of hypothalamic arcuate neurons from iPSCs. The fifth manuscript is a review article in collaboration with the international stakeholders on the promotion of best practices for stem cell research. The sixth manuscript establishes a protocol for the generation of cerebellar organoids and their application in Friedreich’s ataxia disease modeling. The SCTL applied in collaboration with various institutes for Complement-AIRE funding, and if awarded will leverage our iPSC differentiation protocol to generate hypothalamic neurons, as well as cross validate novel protocols and in vitro models established through this collaboration. Ongoing Collaborations: 1) Shuibing Chen (Cornell University): Multi-omic characterization of type 2 diabetes patient iPSC-derived cell types collaboration between NCATS, NHGRI, Cornell and Columbia 2) Claudia Doege (Columbia University): Multi-omic characterization of type 2 diabetes patient iPSC-derived cell types collaboration between NCATS, NHGRI, Cornell and Columbia 3) Lauretta Lacko (Cornell University): Multi-omic characterization of type 2 diabetes patient iPSC-derived cell types collaboration between NCATS, NHGRI, Cornell and Columbia 4) Robert Schwartz (Cornell University): Multi-omic characterization of type 2 diabetes patient iPSC-derived cell types collaboration between NCATS, NHGRI, Cornell and Columbia 5) Ronald Khan (Harvard University): Multi-omic characterization of type 2 diabetes patient iPSC-derived cell types collaboration between NCATS, NHGRI, Cornell and Columbia 6) Stephan Parker (University of Michigan): Multi-omic characterization of type 2 diabetes patient iPSC-derived cell types collaboration between NCATS, NHGRI, Cornell and Columbia 7) Fei Wang (Cornell University): Multi-omic characterization of type 2 diabetes patient iPSC-derived cell types collaboration between NCATS, NHGRI, Cornell and Columbia 8) Leslie Thompson (University of California, Irvine): Huntington’s disease modeling using functional genomics and hPSC-derived astrocytes 9) Daniel Paull (New York Stem Cell Foundation): Role of TCF7L2 in beta cell differentiation and function using iPSCs collaboration between NCATS, NHGRI and NYSCF. 10) Thomas Kent (Texas A&M University): Pleiotropic oxidized carbon nanozymes as new therapeutics for Friedreich’s ataxia treatment 11) Sang Jin Lee (Wake Forest Institute of Regenerative Medicine): Generation of human 3D skeletal muscle composite to study muscle pathophysiology 12) David Bennett (University of Oxford): Transcriptomic analysis of diabetic peripheral neuropathy patient iPSC-derived cell types 13) Anna Moreno (Navega Therapeutics): Testing a Reversible Gene Editing Method for Analgesia using iPSC-derived Sensory Neurons 14) Rosalind Segal (Harvard University): Studies of Chemotherapy Induced Peripheral Neuropathy (CIPN) in iPSC derived peripheral sensory neurons 15) Martin Schneider (University of Maryland Baltimore): Electrophysiological characterization of iPSC-derived neural cell types 16) Clifford Woolf (Harvard): Characterization of iPSC-derived nociceptors Collaboration between SCTL and Harvard 17) Bruce Bean (Harvard University): Characterization of iPSC-derived nociceptors Collaboration between SCTL and Harvard 18) Erick Hernandez-Ochoa (University of Maryland Baltimore): Electrophysiological characterization of iPSC-derived neural cell types 19) Jun-Ho La (University of Texas Medical Branch): Role of GPR37 in pain memory erasure in iPSC-derived sensory neurons. 20) Laura Pollard (Greenwood Genetic Center): Preclinical development of potential gene editing therapy for Free Sialic Acid Storage Disorder collaboration between NCATS and the FSASD Consortium 21) Richard Steet (Greenwood Genetic Center): Preclinical development of potential gene editing therapy for Free Sialic Acid Storage Disorder collaboration between NCATS and the FSASD Consortium 22) Raymond Wang (Children’s Hospital of Orange County): Preclinical development of potential gene editing therapy for Free Sialic Acid Storage Disorder collaboration between NCATS and the FSASD Consortium 23) Monkol Lek (Yale University): Preclinical development of potential gene editing therapy for Free Sialic Acid Storage Disorder collaboration between NCATS and the FSASD Consortium 24) Kostantin Dobrenis (Albert Einstein College of Medicine): Preclinical development of potential gene editing therapy for Free Sialic Acid Storage Disorder collaboration between NCATS and the FSASD Consortium 25) Steven Walkley (Albert Einstein College of Medicine): Preclinical development of potential gene editing therapy for Free Sialic Acid Storage Disorder collaboration between NCATS and the FSASD Consortium 26) Christine Anne-Longin (University of Paris): Preclinical development of potential gene editing therapy for Free Sialic Acid Storage Disorder collaboration between NCATS and the FSASD Consortium 27) Bruno Gasnier (University of Paris): Preclinical development of potential gene editing therapy for Free Sialic Acid Storage Disorder collaboration between NCATS and the FSASD Consortium 28) Ross Marklein (Federal Drug Administration): Development of a platform for manufacturing iPSC-derived mesenchymal stromal cells producing extracellular vesicles for neurodegenerative disease