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BDNF 过表达工程间充质干细胞增强其治疗严重新生缺氧缺血性脑损伤的疗效。

BDNF-Overexpressing Engineered Mesenchymal Stem Cells Enhances Their Therapeutic Efficacy against Severe Neonatal Hypoxic Ischemic Brain Injury.

机构信息

Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.

Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul 06351, Korea.

出版信息

Int J Mol Sci. 2021 Oct 22;22(21):11395. doi: 10.3390/ijms222111395.

DOI:10.3390/ijms222111395
PMID:34768827
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8583727/
Abstract

We investigated whether irradiated brain-derived neurotropic factor (BDNF)-overexpressing engineered human mesenchymal stem cells (BDNF-eMSCs) improve paracrine efficiency and, thus, the beneficial potency of naïve MSCs against severe hypoxic ischemic (HI) brain injury in newborn rats. Irradiated BDNF-eMSCs hyper-secreted BDNF > 10 fold and were >5 fold more effective than naïve MSCs in attenuating the oxygen-glucose deprivation-induced increase in cytotoxicity, oxidative stress, and cell death in vitro. Only the irradiated BDNF-eMSCs, but not naïve MSCs, showed significant attenuating effects on severe neonatal HI-induced short-term brain injury scores, long-term progress of brain infarct, increased apoptotic cell death, astrogliosis and inflammatory responses, and impaired negative geotaxis and rotarod tests in vivo. Our data, showing better paracrine potency and the resultant better therapeutic efficacy of the irradiated BDNF-eMSCs, compared to naïve MSCs, suggest that MSCs transfected with the BDNF gene might represent a better, new therapeutic strategy against severe neonatal HI brain injury.

摘要

我们研究了辐照过的脑源性神经营养因子（BDNF）过表达的工程人类间充质干细胞（BDNF-eMSCs）是否能提高旁分泌效率，从而提高原始 MSCs 对新生大鼠严重缺氧缺血（HI）脑损伤的治疗效果。辐照过的 BDNF-eMSCs 超量分泌 BDNF 超过 10 倍，并且在体外减轻氧葡萄糖剥夺诱导的细胞毒性、氧化应激和细胞死亡方面的效果比原始 MSCs 高 5 倍以上。只有辐照过的 BDNF-eMSCs，而不是原始 MSCs，对新生大鼠严重 HI 引起的短期脑损伤评分、长期脑梗死进展、增加的细胞凋亡、星形胶质细胞增生和炎症反应以及负趋地性和转棒试验受损有显著的改善作用。与原始 MSCs 相比，我们的数据显示辐照过的 BDNF-eMSCs 具有更好的旁分泌效果和更好的治疗效果，表明转染 BDNF 基因的 MSCs 可能是一种治疗严重新生儿 HI 脑损伤的更好的新治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/cd0c2d0edc38/ijms-22-11395-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/07133f8c6ecc/ijms-22-11395-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/dc9867a8ce6a/ijms-22-11395-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/e4cd1f4ffbc6/ijms-22-11395-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/485f85cc2008/ijms-22-11395-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/3ece74e94d59/ijms-22-11395-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/d838a85077de/ijms-22-11395-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/cd0c2d0edc38/ijms-22-11395-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/07133f8c6ecc/ijms-22-11395-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/dc9867a8ce6a/ijms-22-11395-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/e4cd1f4ffbc6/ijms-22-11395-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/485f85cc2008/ijms-22-11395-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/3ece74e94d59/ijms-22-11395-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/d838a85077de/ijms-22-11395-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b65f/8583727/cd0c2d0edc38/ijms-22-11395-g007.jpg

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本文引用的文献

[1]
Immortalization of Mesenchymal Stromal Cells by TERT Affects Adenosine Metabolism and Impairs their Immunosuppressive Capacity.

Stem Cell Rev Rep. 2020-8

[2]
In vivo priming of human mesenchymal stem cells with hepatocyte growth factor-engineered mesenchymal stem cells promotes therapeutic potential for cardiac repair.

Sci Adv. 2020-3-25

[3]
Thrombin Preconditioning Enhances Therapeutic Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells in Severe Neonatal Hypoxic Ischemic Encephalopathy.

Int J Mol Sci. 2019-5-20

[4]
Human UCB-MSCs treatment upon intraventricular hemorrhage contributes to attenuate hippocampal neuron loss and circuit damage through BDNF-CREB signaling.

Stem Cell Res Ther. 2018-11-21

[5]
Hypothermia broadens the therapeutic time window of mesenchymal stem cell transplantation for severe neonatal hypoxic ischemic encephalopathy.

Sci Rep. 2018-5-16

[6]
Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders.

Pediatr Res. 2017-11-1

[7]
Promoting neuroregeneration after perinatal arterial ischemic stroke: neurotrophic factors and mesenchymal stem cells.

Pediatr Res. 2017-11-1

[8]
Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges.

Front Cell Neurosci. 2017-5-8

[9]
Pivotal Role of Brain-Derived Neurotrophic Factor Secreted by Mesenchymal Stem Cells in Severe Intraventricular Hemorrhage in Newborn Rats.

Cell Transplant. 2017-1-24

[10]
Pretreatment with Resveratrol Prevents Neuronal Injury and Cognitive Deficits Induced by Perinatal Hypoxia-Ischemia in Rats.

PLoS One. 2015-11-6

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