Traumatic Brain Injury Research

The Laboratory of Cerebral Injury Protection

The primary focus of our laboratory has been cell-based therapies for TBI using bone marrow stem/stromal cells and we are one of the pioneers in this field. In addition, damage to the brain affects all cell populations including neurons, glia, and vascular elements. Neuroprotective strategies targeting a single injury mechanism or neurons alone may not result in optimal benefits. Pleiotropic or combinatorial agents that act on multiple pathways provide therapeutic potentials to reduce brain damage and to enhance endogenous neurorestoration after TBI, with a final goal of improving functional outcome after brain injury. Neurorestorative strategies are unique in that they act on intact parenchymal cells to stimulate endogenous neurorestorative processes including neurogenesis, angiogenesis, axonal sprouting, oligodendrogenesis, and synaptogenesis to promote functional recovery. We also focus on cell and pharmacological therapies with neurorestorative effects and are trying to develop new therapies that promote neural repair and improve TBI recovery.

Our group is the first to demonstrate that bone marrow mesenchymal stem cell-derived exosomes can improve functional outcomes and spatial learning when given 24 hours after TBI in small animal studies. Collaboration with Dr. Hasan Alam (University of Michigan) has translated these findings into the first clinically relevant large animal model of TBI with promising benefits. When administered 9 hours post-injury, treatment with exosomes attenuated neurologic impairment, promoted faster neurologic recovery, and shortened the time to neurocognitive functional evaluation. As such, exosomes may play a substantial and multifaceted role in providing neuroprotection and/or neuro-restoration depending on the timing of administration. The primary objectives of our ongoing proposal are to assess the therapeutic effects of early administration of exosomes and to determine the neuroprotective mechanisms of exosome administration in a clinically realistic large animal model of TBI and hemorrhagic shock. Our ultimate goal is to successfully translate this strategy into clinical use as an early treatment for TBI.

Recent research indicates that the efficacy of cell therapy for brain injury is likely attributed to the effects of extracellular vesicles including exosomes generated from transplanted stem cells rather than the effects of cell replacement. Exosomes are nanosized extracellular vesicles secreted by nearly all living cells and play a pivotal role in intercellular communication. Exosomes elicit potent cellular responses in the recipient cells via delivery of their cargo including lipids, proteins, RNAs (microRNAs and mRNAs) and other macromolecules. miRNAs function at posttranscriptional levels by regulating gene expression via base-pairing with complementary sequences within mRNA molecules to destabilize the mRNA and induce translational silencing. To enhance the therapeutic efficacy of exosomes, the content and function of exosomes can be modified in various ways. Our current project employs mesenchymal stem-cell-derived naïve exosomes, and designer exosomes engineered with select miRNAs to generate potent exosomes for treatment of brain injuries in animal models of TBI.

Principal Investigators

Ye Xiong, MD, MS, PhD

Xiong Ye 16

Phone: (313) 916-4743

Specialties: Research
Services: Traumatic Brain Injury Research
Board Certification and Education

Education

PhD, Biochemistry and Traumatology, the Third Military Medical University, China, 1994
MS, Biochemistry and Traumatology, the Third Military Medical University, China, 1988
MD, the Third Military Medical University, China, 1985

About Me

Member of the Henry Ford Neuroscience Institute

Personal statement

Traumatic brain injury (TBI) is a significant health concern worldwide. Every year, an estimated 1.7 million people in the United States sustain TBI, and more than 5 million people are coping with disabilities from TBI at an annual cost of more than $60 billion. In addition, TBI is a risk factor for Alzheimer's and Parkinson’s diseases. No effective pharmacological treatments are currently available for TBI. Developing effective therapeutic treatments for TBI is essential. As a neuroscientist, I have a broad background in TBI research, with specific training and expertise in animal models of human TBI, therapeutic treatments, and mechanistic study using a variety of biochemical, histological, and molecular methods with functional outcome as primary endpoints. I am an independent principal investigator with over 20 years of experience actively engaged in translational research in TBI. The objective of my research projects is to test and develop novel therapeutic treatments for TBI and to investigate the molecular mechanisms underlying their therapeutic effects as well as provide essential preclinical information before initiating clinical trials of the novel treatments. My research interests focus primarily on: 1) the cellular and molecular biology of TBI; 2) neuro and vascular protective therapies for TBI; 3) mechanisms of neuroprotection; 4) cell-based and pharmacological neurorestorative therapies for TBI; 5) molecular and cellular mechanisms underlying neurogenesis and angiogenesis and the induction of brain plasticity leading to functional and behavioral recovery after TBI; and 6) exosomes/microRNA for treatment of TBI.

I’ve published over 80 peer-reviewed articles, 13 reviews and book chapters, including Animal Models of TBI in Nature Rev Neurosci. My current National Institutes of health (NIH)-funded research examines the effects of nanosized exosomes isolated from bone marrow mesenchymal stem cells on improving functional recovery by promoting neurovascular remodeling by delivering microRNAs for treatment of TBI. I serve as a manuscript reviewer for 50 peer-reviewed journals, and as a grant reviewer for several funding organizations including the NIH, Department of Defense, and Medical Research Council (UK).

See Publications


Yanlu Zhang

Yanlu Zhang

Specialties: Research
Services: Traumatic Brain Injury Research
Board Certification and Education

Education

MS, Surgery of Abdomen, Medical School of Tongji University, China, 2007
MD, Medical School of Tongji University, China, 2004

About Me

Member of the Henry Ford Neuroscience Institute

Research Interest

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. To date, there are no effective therapies available to promote functional recovery for TBI patients. Thus, there is a compelling need to develop novel therapeutics in order to improve neurological recovery after TBI. Since joining Neurosurgery Research, I’ve undergone extensive training, working with animal models of human TBI, therapeutic treatments, and molecular neurobiology. In addition, I’ve investigated the mechanisms of neuronal regeneration after TBI and performed studies using several novel treatments to improve functional recovery after TBI by promoting neurovascular remodeling in the injured brain. My training has led to collaborative research with other laboratories using various animal models for the study of ischemia/reperfusion, vascular disease, and TBI. I’ve authored 14 published peer-reviewed manuscripts among 27 co-authored papers as well as a book chapter (Angiogenesis and functional recovery after TBI) published in “Vascular mechanisms in CNS trauma” (2014). In addition I’m a reviewer for a number of peer-reviewed journals.

Current Projects/Studies

The goal of our current NIH-funded research is to investigate Vepoloxamer as a novel therapeutic approach to specifically target cerebral microthrombi to improve neurological outcome after TBI. This is the first project to investigate Vepoloxamer as a treatment of TBI.

Our recent study indicates that early (2 h post injury) intravenous administration of Vepoloxamer promotes sensorimotor function and cognitive functional recovery after TBI induced by controlled cortical impact (CCI-TBI), which is associated with its robust effect on reducing cerebral microthrombosis formation and neuroinflammation. Vepoloxamer, a purified form of Poloxamer 188 where impurities associated with renal dysfunction have been removed, is an amphiphilic polyethylene-polypropylene-polyethylene tri-block copolymer that seals membranes and restores plasma membrane integrity in cells damaged by mechanical and electrical injury and in experimental models of muscular dystrophy, heart failure and neurodegenerative disorders. However, to date, there is a paucity of information about Vepoloxamer for treatment of TBI and the mechanisms underlying its therapeutic effects.

Neuroprotection approaches have historically been dominated by targeting neuron-based injury mechanisms as the primary or even exclusive focus of the neuroprotective strategy. The failure of all recent clinical trials for TBI mainly targeting neuroprotection suggests that we need to consider new approaches to the study and development of therapeutic agents. Successful completion of our current proposed research will advance the understanding of the beneficial role of Vepoloxamer-induced prevention of microthrombosis formation in improved functional recovery after TBI, and provide the critical information required for initiating a clinical trial of Vepoloxamer for treatment of TBI. The knowledge gained from this proposal will help develop Vepoloxamer as a rational therapeutic approach to improve neurological outcome, and will have the potential to greatly improve quality of life after TBI as effective pharmacological treatments have not yet been developed.

List of Publications (Since 2018)

  • Zhang Y, Chopp M, Zhang Y, Gang Zhang Z, Lu M, Zhang T, Wu KH, Zhang L, Mahmood A, Xiong Y. Randomized controlled trial of Cerebrolysin's effects on long-term histological outcomes and functional recovery in rats with moderate closed head injury. J Neurosurg. 2019 Sep 6:1-11. doi: 10.3171/2019.6.JNS191027. [Epub ahead of print] PubMed PMID: 31491768.
  • Zhang Y, Chopp M, Zhang ZG, Zhang Y, Zhang L, Lu M, Zhang T, Winter S, Doppler E, Brandstäetter H, Mahmood A, Xiong Y. Cerebrolysin Reduces Astrogliosis and Axonal Injury and Enhances Neurogenesis in Rats After Closed Head Injury. Neurorehabil Neural Repair. 2019 Jan;33(1):15-26. doi: 10.1177/1545968318809916. Epub 2018 Nov 30. PubMed PMID: 30499355.
  • Zhang Y, Chopp M, Rex CS, Simmon VF, Sarraf ST, Zhang ZG, Mahmood A, Xiong Y. A Small Molecule Spinogenic Compound Enhances Functional Outcome and Dendritic Spine Plasticity in a Rat Model of Traumatic Brain Injury. J Neurotrauma. 2019 Feb 15;36(4):589-600. doi: 10.1089/neu.2018.5790. Epub 2018 Sep 6. PubMed PMID: 30014757; PubMed Central PMCID: PMC6354611.
  • Williams AM, Dennahy IS, Bhatti UF, Halaweish I, Xiong Y, Chang P, Nikolian VC, Chtraklin K, Brown J, Zhang Y, Zhang ZG, Chopp M, Buller B, Alam HB. Mesenchymal Stem Cell-Derived Exosomes Provide Neuroprotection and Improve Long-Term Neurologic Outcomes in a Swine Model of Traumatic Brain Injury and Hemorrhagic Shock. J Neurotrauma. 2019 Jan 1;36(1):54-60. doi: 10.1089/neu.2018.5711. Epub 2018 Jul 30. PubMed PMID: 29690826.
  • Zhang Y, Chopp M, Gang Zhang Z, Zhang Y, Zhang L, Lu M, Zhang T, Winter S, Brandstätter H, Mahmood A, Xiong Y. Prospective, randomized, blinded, and placebo-controlled study of Cerebrolysin dose-response effects on long-term functional outcomes in a rat model of mild traumatic brain injury. J Neurosurg. 2018 Nov 1;129(5):1295-1304. doi: 10.3171/2017.6.JNS171007. PubMed PMID: 29303438.
  • Zhang Y, Chopp M, Emanuele M, Zhang L, Zhang ZG, Lu M, Zhang T, Mahmood A, Xiong Y. Treatment of Traumatic Brain Injury with Vepoloxamer (Purified Poloxamer 188). J Neurotrauma. 2018 Feb 15;35(4):661-670. doi: 10.1089/neu.2017.5284. Epub 2018 Jan 11. PubMed PMID: 29121826.

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