Review ArticleHarnessing the power of cell transplantation to target respiratory dysfunction following spinal cord injury
Section snippets
Spinal cord injury
Spinal cord injury (SCI) represents a heterogeneous set of conditions resulting from trauma to the spinal cord. The specific collection of functional deficits after SCI depends on factors such as location, type, and severity of the traumatic event (McDonald and Becker, 2003). Greater than half of all SCI cases occur in the cervical region. Damage in this location can result in respiratory compromise that is physically and psychologically debilitating, because injury frequently disrupts the
Promoting axonal regrowth
Regeneration of damaged axons and reconnection with appropriate post-synaptic structures is a major therapeutic goal for SCI treatment. In addition, promoting sprouting of damaged and/or spared fibers is another important and possibly more easily achievable goal, which would involve generation of novel connections that could underlie meaningful recovery of function (Bareyre et al., 2004). Unfortunately, a host of neuronal-intrinsic (Luo and Park, 2012) and environmental (Bradbury et al., 2002,
Neuronal replacement
Replacement of mature CNS cell types, particularly neurons, is a promising yet challenging endeavor for achieving recovery of damaged neural circuitry. Replacement of PhMNs using transplanted multipotent neural stem cells (NSCs) or lineage-restricted neural progenitor cells (NPCs) has not yet been attempted and faces many challenges, including integration of MNs in the ventral horn, long-distance extension of axonal projections to the periphery, and correct innervation of target muscle. Cell
Glial replacement
Replacement of various glial lineages also holds great promise (Falnikar et al., 2015). Astrocytes play a host of key roles in the CNS, including regulation of extracellular ionic and neurotransmitter homeostasis, active participation in synaptic transmission, delivery of energy substrates to neurons, regulation of blood vessel dynamics and blood brain barrier, generation of extracellular matrix molecules, and expression of neurotrophic factors, amongst a long list of other critical functions (
Gene delivery
Cell transplantation can be used as a vehicle to deliver therapeutic molecules to the injured – or even surrounding intact – spinal cord. A number of candidate cell types, including NSCs, NPCs and mesenchymal stem cells (MSCs), naturally express therapeutically-relevant molecules such as trophic (Neuhuber et al., 2005), immunomodulatory (Pluchino et al., 2003) and axonal growth-inducing (Shih et al., 2014) factors. In addition, cells can be engineered in vitro prior to transplantation to modify
Clinical trial assessing effect of transplantation on respiratory function
A number of clinical trials have been conducted or are currently in progress with SCI patients using a variety of cell types for transplantation, including MSCs, macrophages, NSCs/NPCs, OECs, Schwann cells, and ES cell-derived oligodendrocyte progenitors (Zhu et al., 2014). While the pre-clinical studies detailed in this review have demonstrated the utility of transplantation for targeting breathing compromise, almost no data on respiratory outcome are available in these patient studies.
In a
Conclusions
The studies to date that have investigated the therapeutic potential of transplant-based strategies for addressing respiratory compromise represent only a small fraction of the major body of work that has tested transplantation in models of SCI, despite the critical relevance of breathing dysfunction to patients. Nevertheless, this relatively small number of studies has demonstrated both the power of such an approach and the success of transplantation to target multiple cellular mechanisms for
Acknowledgements, contributions and funding
B.A.C. and M.W.U.: Manuscript writing.
A.C.L.: Manuscript writing; final approval of manuscript.
This work was supported by the Paralyzed Veterans of America Research Foundation (grant #3054 to A.C.L.) and the NINDS (grant #1R01NS079702 to A.C.L.).
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