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Mesenchymal stem cell delivery, survival and migration in a non-invasive system for central nervous system therapeutics
The central nervous system (CNS), consisting of the brain and spinal cord, is a complex network of neuronal and non-neuronal cells that are responsible for sending, receiving and interpreting information from the entire body. Neurodegenerative disease is a general term used for a wide range of acute and chronic conditions that involve neuronal cell death in the CNS. Current treatments are limited to conventional approaches that primarily treat symptoms. The potential for therapy of end-stage CNS degradation is limited, but previous studies have revealed extensive therapeutic windows, prior to the chronic injury phase, that would allow for potential manipulation by exogenous interventions. Human mesenchymal stem cells (hMSCs) have ideal characteristics that grant them clinical potential for cell therapies. They are easily harvested, from healthy bone marrow donors, and manipulated in culture. MSCs have been shown to provide trophic support, lack immunogenicity, and are capable of self-renewal. They also possess the innate ability to be recruited to a tissue lesion by way of chemotactic machinery. The receptor-ligand binding that occurs during this “homing” process initiates inner cellular processes that lead to enhanced production and secretion of growth factors, cytokines, and chemokines. Chemokine stromal cell-derived factor-1 (SDF-1), which is expressed at a wound, interacts with its cognate receptor CXC chemokine receptor 4 (CXCR4), expressed by MSCs, and is an important factor in MSC chemotaxis. The MSC secretome, most notable, brain-derived neurotrophic factor (BDNF), has the potential to contribute to the minimization of cell death and reduction of lesion expansion. Cell-based and gene-based therapy ideology must converge for an efficacious therapy due to the low regenerative capacity of the CNS. The challenges of the mode, timing and location of cell delivery must be further considered. There is potential for an intranasal administration (INA) method due to the unique olfactory region that provides interface between the CNS and the external environment. The current modes of cell delivery are either invasive or inefficient. INA ideology provides a relatively non-invasive method that remains to be controversial by several groups interested in its clinical potential. This study advances upon the knowledge from previous INA studies by (1) the development of a novel device for nasal delivery efficiency, (2) tracking the location and viability of the transplanted hMSCs by bioluminescence (in vivo), as well as, by fluorescence (in situ), and (3) transfecting the hMSCs with a CXCR4 construct to enhance migration to the target tissue. The future steps of this study will be to double transfect hMSCs with a CXCR4-BDNF construct to exploit chemotaxis and enhance the therapeutic potential of the cells for neurodegenerative diseases and injuries.