TY - JOUR
T1 - Modeling neurodegenerative microenvironment using cortical organoids derived from human stem cells
AU - Yan, Yuanwei
AU - Song, Liqing
AU - Bejoy, Julie
AU - Zhao, Jing
AU - Kanekiyo, Takahisa
AU - Bu, Guojun
AU - Zhou, Yi
AU - Li, Yan
N1 - Publisher Copyright:
© Copyright 2018, Mary Ann Liebert, Inc. 2018.
PY - 2018/7
Y1 - 2018/7
N2 - Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and causes cognitive impairment and memory deficits of the patients. The mechanism of AD is not well known, due to lack of human brain models. Recently, mini-brain tissues called organoids have been derived from human induced pluripotent stem cells (hiPSCs) for modeling human brain development and neurological diseases. Thus, the objective of this research is to model and characterize neural degeneration microenvironment using three-dimensional (3D) forebrain cortical organoids derived from hiPSCs and study the response to the drug treatment. It is hypothesized that the 3D forebrain organoids derived from hiPSCs with AD-associated genetic background may partially recapitulate the extracellular microenvironment in neural degeneration. To test this hypothesis, AD-patient derived hiPSCs with presenilin-1 mutation were used for cortical organoid generation. AD-related inflammatory responses, matrix remodeling and the responses to DAPT, heparin (completes with heparan sulfate proteoglycans [HSPGs] to bind Aβ42), and heparinase (digests HSPGs) treatments were investigated. The results indicate that the cortical organoids derived from AD-associated hiPSCs exhibit a high level of Aβ42 comparing with healthy control. In addition, the AD-derived organoids result in an elevated gene expression of proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, upregulate syndecan-3, and alter matrix remodeling protein expression. Our study demonstrates the capacity of hiPSC-derived organoids for modeling the changes of extracellular microenvironment and provides a potential approach for AD-related drug screening.
AB - Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and causes cognitive impairment and memory deficits of the patients. The mechanism of AD is not well known, due to lack of human brain models. Recently, mini-brain tissues called organoids have been derived from human induced pluripotent stem cells (hiPSCs) for modeling human brain development and neurological diseases. Thus, the objective of this research is to model and characterize neural degeneration microenvironment using three-dimensional (3D) forebrain cortical organoids derived from hiPSCs and study the response to the drug treatment. It is hypothesized that the 3D forebrain organoids derived from hiPSCs with AD-associated genetic background may partially recapitulate the extracellular microenvironment in neural degeneration. To test this hypothesis, AD-patient derived hiPSCs with presenilin-1 mutation were used for cortical organoid generation. AD-related inflammatory responses, matrix remodeling and the responses to DAPT, heparin (completes with heparan sulfate proteoglycans [HSPGs] to bind Aβ42), and heparinase (digests HSPGs) treatments were investigated. The results indicate that the cortical organoids derived from AD-associated hiPSCs exhibit a high level of Aβ42 comparing with healthy control. In addition, the AD-derived organoids result in an elevated gene expression of proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, upregulate syndecan-3, and alter matrix remodeling protein expression. Our study demonstrates the capacity of hiPSC-derived organoids for modeling the changes of extracellular microenvironment and provides a potential approach for AD-related drug screening.
KW - degeneration
KW - human induced pluripotent stem cells
KW - neural differentiation
KW - organoids
KW - three-dimensional
UR - http://www.scopus.com/inward/record.url?scp=85049611911&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049611911&partnerID=8YFLogxK
U2 - 10.1089/ten.tea.2017.0423
DO - 10.1089/ten.tea.2017.0423
M3 - Article
C2 - 29361890
AN - SCOPUS:85049611911
SN - 1937-3341
VL - 24
SP - 1125
EP - 1137
JO - Tissue Engineering - Part A
JF - Tissue Engineering - Part A
IS - 13-14
ER -