Generation of homogeneous midbrain organoids with in vivo‐like cellular composition facilitates neurotoxin‐based Parkinson's disease modeling. (28th February 2020)

• Record Type: Journal Article
• Authors: Kwak, Tae Hwan; Kang, Ji Hyun; Hali, Sai; Kim, Jonghun; Kim, Kee‐Pyo; Park, Chanhyeok; Lee, Ju‐Hyun; Ryu, Ha Kyun; Na, Ji Eun; Jo, Junghyun; Je, Hyunsoo Shawn; Ng, Huck‐Hui; Kwon, Jeongwoo; Kim, Nam‐Hyung; Hong, Kwon Ho; Sun, Woong; Chung, Chi Hye; Rhyu, Im Joo; Han, Dong Wook
• Is Part Of: Stem cells. Volume 38:Number 6(2020)
• Page Start: 727
• Page End: 740
• Publication Date: 2020-02-28
• Subjects: differentiation -- embryonic stem cells (ESCs) -- neural differentiation -- Parkinson's disease; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.3163
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: Recent studies have demonstrated the generation of midbrain‐like organoids (MOs) from human pluripotent stem cells. However, the low efficiency of MO generation and the relatively immature and heterogeneous structures of the MOs hinder the translation of these organoids from the bench to the clinic. Here we describe the robust generation of MOs with homogeneous distribution of midbrain dopaminergic (mDA) neurons. Our MOs contain not only mDA neurons but also other neuronal subtypes as well as functional glial cells, including astrocytes and oligodendrocytes. Furthermore, our MOs exhibit mDA neuron‐specific cell death upon treatment with 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine, indicating that MOs could be a proper human model system for studying the in vivo pathology of Parkinson's disease (PD). Our optimized conditions for producing homogeneous and mature MOs might provide an advanced patient‐specific platform for in vitro disease modeling as well as for drug screening for PD. Abstract : This study describes the novel strategy for the robust generation of homogeneous midbrain‐like organoids (MOs) using specific combination of dual SMAD inhibitors and in vitro WNT gradient. DAC3.0 MOs generated by our optimized protocol with in vivo‐like cellular composition are as structurally and functionally mature as the developing midbrain. DAC3.0 MOs with functional glial cells including astrocytes facilitate 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine‐based in vitro disease modeling of PD, suggesting its potential usefulness for an advanced patient‐specific platform for in vitro disease modeling as well as for drug screening for PD.