Project Details
Description
PROJECT SUMMARY
Current stem cell-based treatments for central nervous system (CNS) injuries such as spinal cord injury (SCI),
are severely hampered by poor stem cell survival rates, inefficient integration, loss of neural plasticity, and
uncontrollable differentiation of implanted cells, all of which are caused by the highly inhibitory and inflammatory
microenvironment at disease or injury sites. Specifically, gliosis at the injury site causes the secretion of inhibitory
factors leading to poor axon regeneration and sprouting of surviving neuronal populations, resulting in the
intrinsic limitations of the CNS to regenerate after the initial injury. Therefore, there is an urgent need for effective
strategies to generate a robust population of functional neurons derived from patient-derived stem cells and re-
establish the damaged neural circuitry. To this end, we propose to integrate several fields of research, including
nanotechnology, biomaterials, neuroscience, and stem cell biology, to develop a novel nanoscaffold-based stem
cell assembly platform that allows for the generation of favorable microenvironments during stem cell
implantation and the control of stem cell fate in vivo for potential clinical applications.
To address the fundamental impediment of regeneration associated with CNS injuries and diseases, we
propose to develop injectable 3D-Hybrid SMART neuro-spheroids for enhanced stem cell therapy and effective
treatment of SCI in vivo. The 3D-Hybrid SMART neuro-spheroids are assembled from biodegradable scaffold
nanomaterials enriched with natural neural ECM to promote neural stem cell (NSC) survival and differentiation.
The SMART neuro-spheroids also permit the loading of a bioactive molecule (i.e., Notch inhibitor), resulting in
the synergy between suppressing neuroinhibitory signaling and promoting neural stem cell (NSC) survival and
differentiation. This novel technology platform will be further integrated into two clinically advanced models: i) an
inflammatory CNS organoid model incorporated with microglia, and ii) a spinal cord injury animal model. This
multidisciplinary study will provide a next-generation platform for research and cell therapy in neuro-regenerative
medicine from the perspective of developing a new 3D spheroid assembly method for enhanced stem cell
survival and suppression of inhibitory environment after CNS injuries.
We propose to verify our central hypothesis and achieve our objectives by addressing the following specific
aims: AIM #1 – Develop bioactive and biodegradable-nanoscaffold-based injectable 3D-Hybrid SMART
spheroids; AIM #2 – Investigate deep drug (Notch-i) delivery in SMART spheroids and study neuronal
differentiation of stem cells and axonal growth under neuroinhibitory and immune microenvironments
in vitro; AIM #3 – Determine the therapeutic effects of 3D-Hybrid SMART spheroids on the modulation of
neuroinhibitory microenvironments and the enhancement of SCI functional recovery in vivo. Collectively,
we anticipate that our proposed studies will provide an innovative, highly effective, and robust method for
developing therapeutic interventions for neurological disorders.
Status | Finished |
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Effective start/end date | 6/15/23 → 5/31/24 |
Funding
- National Institute of Neurological Disorders and Stroke: $390,976.00
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