Spinal cord injury (SCI) is a major health care issue in our Veteran population. While rehabilitation medicine provides for some therapeutic improvement for SCI there are no medical interventions that lead to protection of neural tissue or induce regenerative responses. However, a number of cell therapy and small molecule approaches to both protect and promote regeneration have been successful in pre-clinical studies using animal models. Intravenous infusions of bone marrow-derived mesenchymal/stromal stem cells (MSCs) have been demonstrated to produce beneficial effects in repairing tissue damage. Intravenous infusion of MSCs also has beneficial effects in a number of experimental neurological disorders including stroke and spinal cord injury. In some injury or disease models the therapeutic effects of MSC transplantation have been replicated by transplantation of exosomes produced by these MSCs. Exosomes are nanosphere membrane bound particles containing proteins and mRNAs/miRNAs which are highly stable and are capable of being taken up by other cells and altering their function. These recently characterized secreted cellular nanospheres are believed to play an important role in cell-cell communication in both health and disease. Preliminary studies in our lab have found that intravenous infusion of exosomes produced by cultured MSCs can replicate therapeutic effects of MSC infusion in spinal cord injured rats including improved locomotor function and decreased vascular leakage in the spinal cord within one week after intravenous infusion. We propose to determine if these beneficial effects observed early in SCI are sustained and how they compare to MSC infusion. The overall objective of this project is to evaluate the therapeutic potential of intravenously delivered MSC-derived exosomes for spinal cord injury (SCI). Exosomes are more stable and storable than cells and pose no risk of aneuploidy and have a lower possibility of immune rejection. The preclinical work we propose here is directed to provide basic information on safety and the potential therapeutic effects of intravenously delivered MSC- derived exosomes in the context of potential future clinical studies in SCI patients. We currently have ongoing clinical trials in both SCI and stroke using autologous MSCs, and success with the proposed studies could facilitate the development of a clinical study using MSC-derived exosomes for SCI.

Public Health Relevance

Spinal cord injury (SCI) is a major clinical concern for our Veteran population and there are limited therapeutic interventions. Transplantation of mesenchymal stem cells (MSCs) are therapeutically efficacious in animal models of SCI and we currently have an ongoing clinical study using i.v. MSCs in SCI patients. Both i.v. infusion of MSCs reduces lesion size and improves functional recovery in SCI. In some disease models the therapeutic effects of MSCs have been replicated by transplantation of MSC-derived exosomes. Exosomes are small membrane bound nanospheres shed by cells and contain proteins and mRNAs/miRNAs which are capable of being taken up by other cells and altering their function. Our preliminary data suggest that MSC- derived exosomes have a therapeutic effect in SCI. Exosomes are more stable and storable than cells and pose no risk of aneuploidy and have a lower possibility of immune rejection. The overall objective of this project is to evaluate the therapeutic potential of intravenously delivered MSC-derived exosomes in SCI.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX003190-04
Application #
9859326
Study Section
Neurobiology C (NURC)
Project Start
2017-01-01
Project End
2020-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
VA Connecticut Healthcare System
Department
Type
DUNS #
039624291
City
West Haven
State
CT
Country
United States
Zip Code
06516
Lankford, Karen L; Arroyo, Edgardo J; Kocsis, Jeffery D (2017) Chronic TNF? Exposure Induces Robust Proliferation of Olfactory Ensheathing Cells, but not Schwann Cells. Neurochem Res 42:2595-2609
Nakazaki, Masahito; Sasaki, Masanori; Kataoka-Sasaki, Yuko et al. (2017) Intravenous infusion of mesenchymal stem cells inhibits intracranial hemorrhage after recombinant tissue plasminogen activator therapy for transient middle cerebral artery occlusion in rats. J Neurosurg 127:917-926
Torii, Masaaki; Sasaki, Masanori; Chang, Yu-Wen et al. (2017) Detection of vulnerable neurons damaged by environmental insults in utero. Proc Natl Acad Sci U S A 114:2367-2372
Noshiro, Shouhei; Mikami, Takeshi; Kataoka-Sasaki, Yuko et al. (2017) Co-expression of tissue factor and IL-6 in immature endothelial cells of cerebral cavernous malformations. J Clin Neurosci 37:83-90
Nakamura, Hideyuki; Sasaki, Yuichi; Sasaki, Masanori et al. (2017) Elevated brain derived neurotrophic factor (BDNF) levels in plasma but not serum reflect in vivo functional viability of infused mesenchymal stem cells after middle cerebral artery occlusion in rat. J Neurosurg Sci :
Noshiro, Shouhei; Mikami, Takeshi; Kataoka-Sasaki, Yuko et al. (2017) Biological relevance of tissue factor and IL-6 in arteriovenous malformations. Neurosurg Rev 40:359-367