Intranasal Delivery of Mesenchymal Stem Cell Derived Exosomes Loaded with Phosphatase and Tensin Homolog siRNA Repairs Complete Spinal Cord Injury

被引：378

作者：

Guo, Shaowei ^{[1
,2
]}

Perets, Nisim ^{[3
]}

Betzer, Oshra ^{[5
,6
]}

Ben-Shaul, Shahar ^{[1
]}

Sheinin, Anton ^{[3
]}

Michaelevski, Izhak ^{[7
]}

Popovtzer, Rachela ^{[5
,6
]}

Offen, Daniel ^{[3
,4
]}

Levenberg, Shulamit ^{[1
]}

机构：

[1] Technion Israel Inst Technol, Dept Biomed Engn, IL-3200003 Haifa, Israel

[2] Shantou Univ, Affiliated Hosp 1, Med Coll, Shantou 515041, Peoples R China

[3] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel

[4] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel

[5] Bar Ilan Univ, Fac Engn, IL-5290002 Ramat Gan, Israel

[6] Bar Ilan Univ, Inst Nanotechnol & Adv Mat, IL-5290002 Ramat Gan, Israel

[7] Ariel Univ, Dept Mol Biol, IL-40700 Ariel, Israel

来源：

ACS NANO | 2019年 / 13卷 / 09期

基金：

以色列科学基金会;

关键词：

intranasal; exosome; PTEN siRNA; targeted delivery; functional recovery; complete spinal cord injury; PROMOTE FUNCTIONAL RECOVERY; STROMAL CELLS; NEUROVASCULAR PLASTICITY; REGENERATIVE GROWTH; MEDIATED DELIVERY; LOCAL TRANSLATION; RNA INTERFERENCE; TRAUMATIC BRAIN; MOTOR FUNCTION; AXON GROWTH;

D O I：

10.1021/acsnano.9b01892

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Individuals with spinal cord injury (SCI) usually suffer from permanent neurological deficits, while spontaneous recovery and therapeutic efficacy are limited. Here, we demonstrate that when given intranasally, exosomes derived from mesenchymal stem cells (MSC-Exo) could pass the blood brain barrier and migrate to the injured spinal cord area. Furthermore, MSC-Exo loaded with phosphatase and tensin homolog small interfering RNA (ExoPTEN) could attenuate the expression of PTEN in the injured spinal cord region following intranasal administrations. In addition, the loaded MSC-Exo considerably enhanced axonal growth and neovascularization, while reducing microgliosis and astrogliosis. The intranasal ExoPTEN therapy could also partly improve structural and electrophysiological function and, most importantly, significantly elicited functional recovery in rats with complete SCI. The results imply that intranasal ExoPTEN may be used clinically to promote recovery for SCI individuals.

引用

页码：10015 / 10028

页数：14

共 97 条

[1] Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes [J].

Alvarez-Erviti, Lydia ;

Seow, Yiqi ;

Yin, HaiFang ;

Betts, Corinne ;

Lakhal, Samira ;

Wood, Matthew J. A. .

NATURE BIOTECHNOLOGY, 2011, 29 (04) :341-U179

[2] Inflammogenesis of Secondary Spinal Cord Injury [J].

Anwar, M. Akhtar ;

Al Shehabi, Tuqa S. ;

Eid, Ali H. .

FRONTIERS IN CELLULAR NEUROSCIENCE, 2016, 10

[3]

Aung Wint Yan, 2013, Imaging Med, V5, P427

[4] Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species [J].

Baglio, Serena Rubina ;

Rooijers, Koos ;

Koppers-Lalic, Danijela ;

Verweij, Frederik J. ;

Lanzon, M. Perez ;

Zini, Nicoletta ;

Naaijkens, Benno ;

Perut, Francesca ;

Niessen, Hans W. M. ;

Baldini, Nicola ;

Pegtel, D. Michiel .

STEM CELL RESEARCH & THERAPY, 2015, 6

[5] A SENSITIVE AND RELIABLE LOCOMOTOR RATING-SCALE FOR OPEN-FIELD TESTING IN RATS [J].

BASSO, DM ;

BEATTIE, MS ;

BRESNAHAN, JC .

JOURNAL OF NEUROTRAUMA, 1995, 12 (01) :1-21

[6]

Betzer O., 2018, P SOC PHOTO-OPT INS, P44

[7]

Betzer O., 2017, P SOC PHOTO-OPT INS, P10077

[8] In Vivo Neuroimaging of Exosomes Using Gold Nanoparticles [J].

Betzer, Oshra ;

Perets, Nisim ;

Ange, Ariel ;

Motiei, Menachem ;

Sadan, Tamar ;

Yadid, Gal ;

Offen, Daniel ;

Popovtzer, Rachela .

ACS NANO, 2017, 11 (11) :10883-10893

[9] The effect of nanoparticle size on the ability to cross the blood-brain barrier: an in vivo study [J].

Betzer, Oshra ;

Shilo, Malka ;

Opochinsky, Renana ;

Barnoy, Eran ;

Motiei, Menachem ;

Okun, Eitan ;

Yadid, Gal ;

Popovtzer, Rachela .

NANOMEDICINE, 2017, 12 (13) :1533-1546

[10] In-vitro Optimization of Nanoparticle-Cell Labeling Protocols for In-vivo Cell Tracking Applications [J].

Betzer, Oshra ;

Meir, Rinat ;

Dreifuss, Tamar ;

Shamalov, Katerina ;

Motiei, Menachem ;

Shwartz, Amit ;

Baranes, Koby ;

Cohen, Cyrille J. ;

Shraga-Heled, Niva ;

Ofir, Racheli ;

Yadid, Gal ;

Popovtzer, Rachela .

SCIENTIFIC REPORTS, 2015, 5

← 1 2 3 4 5 6 7 8 9 10 →