PMID- 34899919
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20211215
IS  - 1687-966X (Print)
IS  - 1687-9678 (Electronic)
VI  - 2021
DP  - 2021
TI  - Extracellular Vesicles Released from Neprilysin Gene-Modified Human Umbilical 
      Cord-Derived Mesenchymal Stem Cell Enhance Therapeutic Effects in an Alzheimer's 
      Disease Animal Model.
PG  - 5548630
LID - 10.1155/2021/5548630 [doi]
LID - 5548630
AB  - Alzheimer's disease (AD) animal studies have reported that mesenchymal stem cells 
      (MSCs) have therapeutic effects; however, clinical trial results are 
      controversial. Neprilysin (NEP) is the main cleavage enzyme of beta-amyloid (Abeta), 
      which plays a major role in the pathology and etiology of AD. We evaluated 
      whether transplantation of MSCs with NEP gene modification enhances the 
      therapeutic effects in an AD animal model and then investigated these 
      pathomechanisms. We manufactured NEP gene-enhanced human umbilical cord-derived 
      mesenchymal stem cells (hUC-MSCs) and intravenously transplanted them in Abeta 
      (1-42)-injected AD animal models. We compared the differences in behavioral tests 
      and immunohistochemical assays between four groups: normal, Abeta (1-42) injection, 
      naive hUC-MSCs, and NEP-enhanced hUC-MSCs. Both naive and NEP-enhanced hUC-MSC 
      groups showed significant improvements in memory compared to the Abeta (1-42) 
      injection group. There was no significant difference between naive and 
      NEP-enhanced hUC-MSC groups. There was a significant decrease in Congo red, 
      BACE-1, GFAP, and Iba-1 and a significant increase in BDNF, NeuN, and NEP in both 
      hUC-MSC groups compared to the Abeta (1-42) injection group. Among them, BDNF, NeuN, 
      GFAP, Iba-1, and NEP showed more significant changes in the NEP-enhanced hUC-MSC 
      group than in the naive group. After stem cell injection, stem cells were not 
      found. Extracellular vesicles (EVs) were equally observed in the hippocampus in 
      the naive and NEP-enhanced hUC-MSC groups. However, the EVs of NEP-enhanced 
      hUC-MSCs contained higher amounts of NEP as compared to the EVs of naive 
      hUC-MSCs. Thus, hUC-MSCs affect AD animal models through stem cell-released EVs. 
      Although there was no significant difference in cognitive function between the 
      hUC-MSC groups, NEP-enhanced hUC-MSCs had superior neurogenesis and 
      anti-inflammation properties compared to naive hUC-MSCs due to increased NEP in 
      the hippocampus by enriched NEP-possessing EVs. NEP gene-modified MSCs that 
      release an increased amount of NEP within EVs may be a promising therapeutic 
      option in AD treatment.
CI  - Copyright (c) 2021 HyeJu Jeong et al.
FAU - Jeong, HyeJu
AU  - Jeong H
AD  - Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, 
      Gyeonggi 13496, Republic of Korea.
FAU - Kim, Ok Joon
AU  - Kim OJ
AUID- ORCID: 0000-0002-7333-0647
AD  - Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, 
      Gyeonggi 13496, Republic of Korea.
FAU - Oh, Seung-Hun
AU  - Oh SH
AD  - Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, 
      Gyeonggi 13496, Republic of Korea.
FAU - Lee, Sanghoon
AU  - Lee S
AD  - Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, 
      Gyeonggi 13496, Republic of Korea.
FAU - Reum Lee, Han A
AU  - Reum Lee HA
AD  - Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, 
      Gyeonggi 13496, Republic of Korea.
FAU - Lee, Kee Ook
AU  - Lee KO
AD  - Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, 
      Gyeonggi 13496, Republic of Korea.
FAU - Lee, Boo-Yong
AU  - Lee BY
AD  - Department of Food Science and Biotechnology, College of Life Science, CHA 
      University, Seongnam, Gyeonggi 13488, Republic of Korea.
FAU - Kim, Nam Keun
AU  - Kim NK
AD  - Department of Biomedical Science, College of Life Science, CHA University, 
      Seongnam, Gyeonggi 13496, Republic of Korea.
LA  - eng
PT  - Journal Article
DEP - 20211203
PL  - United States
TA  - Stem Cells Int
JT  - Stem cells international
JID - 101535822
PMC - PMC8664527
COIS- There are no conflicts of interest to declare for all authors.
EDAT- 2021/12/14 06:00
MHDA- 2021/12/14 06:01
PMCR- 2021/12/03
CRDT- 2021/12/13 17:57
PHST- 2021/02/25 00:00 [received]
PHST- 2021/05/12 00:00 [revised]
PHST- 2021/11/02 00:00 [accepted]
PHST- 2021/12/13 17:57 [entrez]
PHST- 2021/12/14 06:00 [pubmed]
PHST- 2021/12/14 06:01 [medline]
PHST- 2021/12/03 00:00 [pmc-release]
AID - 10.1155/2021/5548630 [doi]
PST - epublish
SO  - Stem Cells Int. 2021 Dec 3;2021:5548630. doi: 10.1155/2021/5548630. eCollection 
      2021.