PSEN1 E280A Cholinergic-like Neurons and Cerebral Spheroids Derived from Mesenchymal Stromal Cells and from Induced Pluripotent Stem Cells Are Neuropathologically Equivalent.
PSEN1 E280A Cholinergic-like Neurons and Cerebral Spheroids Derived from Mesenchymal Stromal Cells and from Induced Pluripotent Stem Cells Are Neuropathologically Equivalent.
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PSEN1 E280A胆碱能神经元和源自间充质基质细胞和诱导多能干细胞的脑球体是神经病理学上等效的。
DOI：
10.3390/ijms24108957
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发表时间：
2023-05-18
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
阿尔茨海默病（AD）是一种以胆碱能神经元严重丧失为特征的慢性神经系统疾病。目前，对神经元丧失的不完全了解阻碍了家族性AD （FAD）的治愈性治疗。因此，体外建立FAD模型是研究胆碱能脆弱性的必要手段。此外，为了加快发现延缓阿尔茨海默病发病和减缓阿尔茨海默病进展的疾病修饰疗法，我们依赖于可靠的疾病模型。诱导多能干细胞（iPSCs）衍生的胆碱能神经元（ChNs）虽然信息丰富，但耗时、不划算、劳动密集型。迫切需要AD建模的其他资源。将野生型和早衰素（PSEN）1 p.E280A成纤维细胞来源的iPSCs、经血来源的月经间质细胞（MenSCs）和脐带来源的Wharton Jelly’s间充质间质细胞（WJ-MSCs）分别在Cholinergic-N-Run和Fast-N-Spheres V2培养基中培养，分别获得WT和PSEN 1 e . 280a胆碱能样神经元（ChLNs, 2D）和脑样球（CSs, 3D），并评估ChLNs/CSs是否能复制FAD病理。我们发现，无论组织来源如何，ChLNs/CSs都成功再现了AD表型。PSEN 1 E280A ChLNs/CSs显示iAPPβ片段的积累，产生eAβ42，呈现TAU磷酸化，显示OS标记（例如，oxj -1, p-JUN），显示ΔΨm的丢失，显示细胞死亡标记（例如，TP53， PUMA, CASP3），并显示对ACh刺激的功能失调的Ca2+内流反应。然而，来自MenSCs和WJ-MSCs的PSEN 1 E280A 2D和3D细胞比来自突变iPSCs的ChLNs（35天）更有效和更快地复制FAD神经病理（11天）。从机制上讲，MenSCs和WJ-MSCs在体外再生FAD方面与iPSCs是相同的细胞类型。
Alzheimer’s disease (AD) is a chronic neurological condition characterized by the severe loss of cholinergic neurons. Currently, the incomplete understanding of the loss of neurons has prevented curative treatments for familial AD (FAD). Therefore, modeling FAD in vitro is essential for studying cholinergic vulnerability. Moreover, to expedite the discovery of disease-modifying therapies that delay the onset and slow the progression of AD, we depend on trustworthy disease models. Although highly informative, induced pluripotent stem cell (iPSCs)-derived cholinergic neurons (ChNs) are time-consuming, not cost-effective, and labor-intensive. Other sources for AD modeling are urgently needed. Wild-type and presenilin (PSEN)1 p.E280A fibroblast-derived iPSCs, menstrual blood-derived menstrual stromal cells (MenSCs), and umbilical cord-derived Wharton Jelly’s mesenchymal stromal cells (WJ-MSCs) were cultured in Cholinergic-N-Run and Fast-N-Spheres V2 medium to obtain WT and PSEN 1 E280A cholinergic-like neurons (ChLNs, 2D) and cerebroid spheroids (CSs, 3D), respectively, and to evaluate whether ChLNs/CSs can reproduce FAD pathology. We found that irrespective of tissue source, ChLNs/CSs successfully recapitulated the AD phenotype. PSEN 1 E280A ChLNs/CSs show accumulation of iAPPβ fragments, produce eAβ42, present TAU phosphorylation, display OS markers (e.g., oxDJ-1, p-JUN), show loss of ΔΨm, exhibit cell death markers (e.g., TP53, PUMA, CASP3), and demonstrate dysfunctional Ca2+ influx response to ACh stimuli. However, PSEN 1 E280A 2D and 3D cells derived from MenSCs and WJ-MSCs can reproduce FAD neuropathology more efficiently and faster (11 days) than ChLNs derived from mutant iPSCs (35 days). Mechanistically, MenSCs and WJ-MSCs are equivalent cell types to iPSCs for reproducing FAD in vitro.
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影响因子：
5
作者：
Gezen-Ak, Duygu;Yurttas, Zuhal;Camoglu, Tugay;Dursun, Erdinc
通讯作者：
Dursun, Erdinc
影响因子：
1.2
作者：
Frederiksen, Henriette R.;Holst, Bjorn;Schmid, Benjamin
通讯作者：
Schmid, Benjamin
影响因子：
9.8
作者：
Lazic, Stanley E.;Clarke-Williams, Charlie J.;Munafo, Marcus R.
通讯作者：
Munafo, Marcus R.
DOI：
10.1038/s41572-021-00269-y
发表时间：
2021-05-13
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
Knopman DS;Amieva H;Petersen RC;Chételat G;Holtzman DM;Hyman BT;Nixon RA;Jones DT
通讯作者：
Jones DT
影响因子：
9.3
作者：
Hampel H;Vergallo A;Aguilar LF;Benda N;Broich K;Cuello AC;Cummings J;Dubois B;Federoff HJ;Fiandaca M;Genthon R;Haberkamp M;Karran E;Mapstone M;Perry G;Schneider LS;Welikovitch LA;Woodcock J;Baldacci F;Lista S;Alzheimer Precision Medicine Initiative (APMI)
通讯作者：
Alzheimer Precision Medicine Initiative (APMI)