RIL: Research

Neural Stem Cells and Brain Repair | In Situ Tissue Regeneration After Stroke | Cellular MRI | Mesoscale Tissue Connectivity in Human Brain Tissue

Neural Stem Cells and Brain Repair

During brain development, neural stem cells (NSCs) produce brain cells that are responsible for our behavior. After a stroke, the damaged tissue surrounding the core of the infarct is severely damaged and many neurons are lost. To improve the functioning of this peri-infarct tissue, we implant NSCs that can develop into adult brain cells and replace lost cells. These cells can improve functioning of this tissue in many ways, for instance by creating new neurons that integrate with others to support signaling across the brain. NSCs also secrete chemical factors that rescue dysfunctional cells and they enhance the formation of small blood vessels. Our aims are to define the therapeutic parameters of the cell injection and investigate mechanisms that can explain how these cells are improving behavioral impairments.

Key References:

Ghuman, H., Perry, N., Grice, L., Gerwig, M., Moorhead, J., Nitzsche, F., Poplawsky, A., Ambrosio, F., Modo, M. Physical therapy exerts sub-additive and suppressive effects on intracerebral neural stem cell implantation in a rat model of stroke. Journal of Cerebral Blood Flow and Metabolism. 2021, 41(1): 1-18. PMID: 34826373.

Rossetti, T., Nicholls, F., Modo, M. Intracerebral cell transplantation: Preparation and characterization of cell suspensions. Cell Transplantation. 2016; 25: 645-664. PMID: 26720923.

Wahlberg, B., Ghuman, H., Liu, J.R., Modo, M. Ex vivo biomechanical characterization of syringe-needle ejections for intracerebral cell delivery. Scientific Reports. 2018; 8: 9194. PMID: 29907825.

Chou, C.H. & Modo, M. Characterization of gene expression changes in human neural stem cells and endothelial cells modeling a neurovascular environment. Brain Research Bulletin. 2020; 158: 9-19. PMID: 32092433.

In Situ Tissue Regeneration After Stroke

Stroke produces a dramatic loss of cells in the brain that at its core leads to tissue cavitation, where even the support structure (the so called extra-cellular matrix) is degraded. Building on our efforts with cell transplantation for brain repair, we aim to replace this lost tissue by introducing bioscaffolds made from extracellular matrix (ECM) to provide a novel support structure. These bioscaffolds are gradually degraded by the immune system over time, while releasing chemical factors that attract endogenous progenitor cells. The invasion of novel brain cells into the infarct core leads to the development of a new brain tissue in the cavity. Our past efforts have been geared towards establishing the feasibility of this approach, while our current investigations are focused on the therapeutic potential of this approach as a treatment modality for chronic stroke.

Key References:

Ghuman, H., Matta, R., Tompkins, A., Nitzsche, F., Badylak, S., Gonzalez, A., Modo, M. ECM hydrogel improves the delivery and retention of stem cell encapsulating PEG microspheres in a stroke cavity. Brain Research Bulletin. 2021, 168-120-137. PMID: 33373665.

Damian, C., Ghuman, H., Mauney, C., Azar, R., Reinartz, J., Badylak, S.F., Modo, M. Post-stroke timing of ECM hydrogel implantation affects biodegradation and tissue restoration. International Journal for Molecular Sciences. 2021, 22(21): 11372. PMID: 34768800.

Ghuman, H., Mauney, C., Donnelly, J., Massensini, A., Badylak, S.F., Modo, M. Biodegradation of ECM hydrogel promotes endogenous brain tissue restoration in a rat model of stroke. Acta Biomaterialia 2018; 80: 66-84. PMID: 30232030.

Cellular MRI

The improvement of behavioral functions after an intracerebral injection of neural stem cells is time-dependent process. It takes several weeks before changes in behavior are apparent and this is a gradual process that last several weeks at least. However, during this time of recovery, it is currently not possible to investigate over time in the same host what these cells are doing. Non-invasive imaging however can provide an insight into these brains, but conventional techniques do not afford a distinction of implanted cells from the host tissue. We are therefore using MRI contrast agents that are incorporated into the cells prior to implantation. These MRI contrast agents (e.g. Gadolinium nanoparticles, Fluorine nanoemulsions) are detectable against the background of the normal brain and hence allow us to map the distribution of cells over time. The ultimate aim of these experiments is to develop tools that would allow us to study how the evolution of the distribution, survival and differentiation of implanted cells relates to observed changes in behavioral impairments.

Key References:

Nicholls, F., Rotz, M.W., Ling, W., Ghuman, H., MacRenaris, K.W., Meade, T.J., Modo, M. DNA-Gadolinium-Gold nanoparticles for in vivo T1 MR imaging of transplanted human neural stem cells. Biomaterials. 2016; 77: 291-306. PMID: 26615367.

Nicholls, F., Ling, W., Ferrauto, G., Aime, S., Modo, M. Simultaneous MR imaging for tissue engineering in a rat model of stroke. Scientific Reports. 2015; 5: 14597. PMID: 26419200.

Ghuman, H., Hitchens, K., Modo, M. A systematic optimization of 19F MR image acquisition to detect macrophage invasion into an ECM hydrogel implanted in the stroke-damaged brain. Neuroimage. 2019; 202. PMID: 31408717.

Modo, M., Ghuman, H., Azar, R., Krafty, R., Badylak, S.F., Hitchens, T.K. Mapping the acute time course of immune cell infiltration into an ECM hydrogel in a rat model of stroke using 19F MRI. Biomaterials. 2022, 282: 121386. PMID: 35093825.

Mesoscale Tissue Connectivity in Human Brain Tissue

The anatomical composition of the human brain has mostly relied on immunohistochemical analyses. However, histology is reliant on thin tissue sections that do not easily afford the tracing of connections. In contrast, MRI-based tractography is focused on macroscopic connections of white matter tracts, but in adequate to trace grey matter connectivity. To bridge this methodological abyss, we have developed mesoscale connectivity using high resolution (100 m isotropic) MRI to probe hippocampal connectivity. This approach can be extended to other brain regions to investigate grey matter connectivity, as well as how fibers from white matter extend into grey matter regions.

Key References:

Ke, J., Foley, L., Hitchens, T.K., Richardson, M., Modo, M. Ex vivo mesoscopic diffusion MRI correlates with seizure frequency in patients with uncontrolled temporal lobe epilepsy. Human Brain Mapping 2020; 41: 4529-4548. PMID: 326221364.

Ly, M., Foley, L., Manivannan, A., Hitchens, T.K., Richardson, M., Modo, M. Mesoscale diffusion MR imaging of the ex vivo human hippocampus. Human Brain Mapping. 2020; 41(15):4200-4218. PMID: 32621364.