Publications by authors named "Melissa Alvarado-Velez"

6 Publications

  • Page 1 of 1

Enriching neural stem cell and anti-inflammatory glial phenotypes with electrical stimulation after traumatic brain injury in male rats.

J Neurosci Res 2021 Jul 26;99(7):1864-1884. Epub 2021 Mar 26.

Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA.

Traumatic brain injury (TBI) by an external physical impact results in compromised brain function via undesired neuronal death. Following the injury, resident and peripheral immune cells, astrocytes, and neural stem cells (NSCs) cooperatively contribute to the recovery of the neuronal function after TBI. However, excessive pro-inflammatory responses of immune cells, and the disappearance of endogenous NSCs at the injury site during the acute phase of TBI, can exacerbate TBI progression leading to incomplete healing. Therefore, positive outcomes may depend on early interventions to control the injury-associated cellular milieu in the early phase of injury. Here, we explore electrical stimulation (ES) of the injury site in a rodent model (male Sprague-Dawley rats) to investigate its overall effect on the constituent brain cell phenotype and composition during the acute phase of TBI. Our data showed that a brief ES for 1 hr on day 2 of TBI promoted anti-inflammatory phenotypes of microglia as assessed by CD206 expression and increased the population of NSCs and Nestin astrocytes at 7 days post-TBI. Also, ES effectively increased the number of viable neurons when compared to the unstimulated control group. Given the salience of microglia and neural stem cells for healing after TBI, our results strongly support the potential benefit of the therapeutic use of ES during the acute phase of TBI to regulate neuroinflammation and to enhance neuroregeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jnr.24834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360147PMC
July 2021

Immuno-suppressive hydrogels enhance allogeneic MSC survival after transplantation in the injured brain.

Biomaterials 2021 01 28;266:120419. Epub 2020 Sep 28.

Dept. of Biomedical Engineering, Duke University, Durham, NC, 27708, USA. Electronic address:

Traumatic brain injury (TBI) triggers multiple biochemical and cellular processes that exacerbate brain tissue damage through a secondary injury. Therapies that prevent or limit the evolution of secondary injury could significantly reduce the neurological deficits associated with TBI. Mesenchymal stem cell (MSC) transplantation after TBI can ameliorate neurological deficits by modulating inflammation and enhancing the expression of neurotrophic factors. However, transplanted MSCs can be actively rejected by host immune responses, such as those mediated by cytotoxic CD8 T cells, thereby limiting their therapeutic efficacy. Here, we designed an agarose hydrogel that releases Fas ligand (FasL), a protein that can induce apoptosis of cytotoxic CD8 T cells. We studied the immunosuppressive effect of this hydrogel near the allogeneic MSC transplantation site and its impact on the survival of transplanted MSCs in the injured brain. Agarose-FasL hydrogels locally reduced the host cytotoxic CD8 T cell population and enhanced the survival of allogeneic MSCs transplanted near the injury site. Furthermore, the expression of crucial neurotrophic factors was elevated in the injury penumbra, suggesting an enhanced therapeutic effect of MSCs. These results suggest that the development of immunosuppressive hydrogels for stem cell delivery can enhance the benefits of stem cell therapy for TBI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2020.120419DOI Listing
January 2021

Discovery of Lipidome Alterations Following Traumatic Brain Injury via High-Resolution Metabolomics.

J Proteome Res 2018 06 27;17(6):2131-2143. Epub 2018 Apr 27.

Wallace H Coulter Department of Biomedical Engineering , Georgia Institute of Technology , Atlanta , Georgia 30332 , United States.

Traumatic brain injury (TBI) can occur across wide segments of the population, presenting in a heterogeneous manner that makes diagnosis inconsistent and management challenging. Biomarkers offer the potential to objectively identify injury status, severity, and phenotype by measuring the relative concentrations of endogenous molecules in readily accessible biofluids. Through a data-driven, discovery approach, novel biomarker candidates for TBI were identified in the serum lipidome of adult male Sprague-Dawley rats in the first week following moderate controlled cortical impact (CCI). Serum samples were analyzed in positive and negative modes by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). A predictive panel for the classification of injured and uninjured sera samples, consisting of 26 dysregulated species belonging to a variety of lipid classes, was developed with a cross-validated accuracy of 85.3% using omniClassifier software to optimize feature selection. Polyunsaturated fatty acids (PUFAs) and PUFA-containing diacylglycerols were found to be upregulated in sera from injured rats, while changes in sphingolipids and other membrane phospholipids were also observed, many of which map to known secondary injury pathways. Overall, the identified biomarker panel offers viable molecular candidates representing lipids that may readily cross the blood-brain barrier (BBB) and aid in the understanding of TBI pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jproteome.8b00068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341947PMC
June 2018

Chondroitin Sulfate Glycosaminoglycan Matrices Promote Neural Stem Cell Maintenance and Neuroprotection Post-Traumatic Brain Injury.

ACS Biomater Sci Eng 2017 Mar 13;3(3):420-430. Epub 2017 Feb 13.

Regenerative Bioscience Center, The University of Georgia, 425 River Road, ADS Complex, Athens, Georgia 30602, United States.

There are currently no effective treatments for moderate-to-severe traumatic brain injuries (TBIs). The paracrine functions of undifferentiated neural stem cells (NSCs) are believed to play a significant role in stimulating the repair and regeneration of injured brain tissue. We therefore hypothesized that fibroblast growth factor (FGF2) enriching chondroitin sulfate glycosaminoglycan (CS-GAG) matrices can maintain the undifferentiated state of neural stem cells (NSCs) and facilitate brain tissue repair subacutely post-TBI. Rats subjected to a controlled cortical impactor (CCI) induced TBI were intraparenchymally injected with CS-GAG matrices alone or with CS-GAG matrices containing PKH26GL labeled allogeneic NSCs. Nissl staining of brain tissue 4 weeks post-TBI demonstrated the significantly enhanced ( < 0.05) tissue protection in CS-GAG treated animals when compared to TBI only control, and NSC only treated animals. CS-GAG-NSC treated animals demonstrated significantly enhanced ( < 0.05) FGF2 retention, and maintenance of PKH26GL labeled NSCs as indicated by enhanced Sox1+ and Ki67+ cell presence over other differentiated cell types. Lastly, all treatment groups and sham controls exhibited a significantly ( < 0.05) attenuated GFAP+ reactive astrocyte presence in the lesion site when compared to TBI only controls.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsbiomaterials.6b00805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937277PMC
March 2017

Hydrogels as carriers for stem cell transplantation.

IEEE Trans Biomed Eng 2014 May;61(5):1474-81

Stem cells are a promising source for cell replacement therapy for several degenerative conditions. However, a number of limitations such as low cell survival, uncontrolled and/or low differentiation, induction of host immune response, and the risk of teratoma formation remain as challenges. In this review, we explore the utility of hydrogels as carriers for stem cell delivery and their potential to overcome some of the current limitations in stem cell therapy. We focus on in situ gelling hydrogels, and also discuss other strategies to modulate the immune response to promote controlled stem cell differentiation. Immunomodulatory hydrogels and gels designed to promote cell survival and integration into the host site will likely have a significant effect on enhancing the efficacy of stem cell transplantation as a therapy for debilitating degenerative diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TBME.2014.2305753DOI Listing
May 2014

Oncogenic effects of miR-10b in glioblastoma stem cells.

J Neurooncol 2013 Apr 10;112(2):153-63. Epub 2013 Jan 10.

Departments of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.

MicroRNAs and cancer stem cells have emerged as critical players in glioblastoma, one of the deadliest human cancers. In this study, we investigated the expression and function of microRNA-10b in glioblastoma cells and stem cells. An analysis of The Cancer Genome Atlas data revealed a correlation between high miR-10b levels and poor prognosis in glioblastoma patients. We measured the levels of miR-10b and found that it is upregulated in human glioblastoma tissues, glioblastoma cell and stem cell lines as compared to normal human tissues or astrocytes. Inhibition of miR-10b with a specific antagomir inhibited the proliferation of glioblastoma established and stem cell lines. Inhibition of miR-10b strongly reduced cell invasion and migration in glioblastoma cell and stem cell lines while overexpression of miR-10b induced cell migration and invasion. We also investigated several predicted targets of miR-10b but could not verify any of them experimentally. Additionally, miR-10b inhibition significantly decreased the in vivo growth of stem cell-derived orthotopic GBM xenografts. Altogether, our findings confirm the oncogenic effects of miR-10b in GBM cells and show for the first time a role of this microRNA in GBM stem cells. Targeting miR-10b might therefore inhibit glioblastoma stem cells, which are thought to be at the origin of glioblastoma and to contribute its recurrence and resistance to therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-013-1047-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609924PMC
April 2013
-->