Effect of organic chalcones on human cell lines and hPSC-derived cell types

National Center For Advancing Translational Sciences

Investigators

Abstract

Parasitic nematodes infect plants and animals (including humans) and cause economic loses not to mention human suffering. The World Health Organization estimates that 2 billion people carry parasitic nematodes. Although parasitic nematodes present a major economic burden, not much has been developed in the way of mechanisms of control. Novel organic chalcones which are effective at controlling parasitic nematodes have been developed as safer alternatives to current pest control strategies. Here we aim to determine whether these chalcones may have negative effects on human cell lines and/or human pluripotent stem cell (hPSC)-derived cell types. 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. In this collaboration, the SCTL evaluated the effect of various chalcones on cell viability and proliferation as single reagents and in combination to determine potential toxicity in human cells. This collaboration has resulted in a the submission of a manuscript titled “Nematicide chalcones act synergistically on Caenorhabditis elegans and Meloidogyne incognita without disrupting soil microbial diversity and with limited toxicity to human cells” that is currently in revision for resubmission to Molecules. 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