Axonal growth and connectivity from neural stem cell grafts in models of spinal cord injury
Introduction
Spinal cord injury (SCI) results in the death of neurons at the injury site and the loss of axons that carry signals to and from the brain. Axons of the injured adult central nervous system (CNS) exhibit little ability to spontaneously regenerate, often resulting in permanent functional deficits below the level of injury [1]. For more than a decade, neural stem cells (NSCs) or neural precursor cells (NPCs) have been an attractive cell source for the treatment of SCI, because they have the potential to replace lost neurons and glia, and to restore disrupted connectivity at lesion sites. Recently we have come to appreciate that grafts of NSCs to spinal cord lesion sites are able to extend numerous new axons into the host spinal cord for long distances, and to receive inputs from injured host axons. On the basis of this bi-directional growth of axons and establishment of reciprocal synapses, NSCs form new relays between separated segments of the spinal cord after injury (Fig. 1).
NSCs or NPCs can be isolated from the developing CNS, or derived from pluripotent stem cells, including embryonic stem (ES) cells or induced pluripotent stem (iPS) cells. Here, we systematically review NSC transplantation studies in SCI research, with an emphasis on axonal growth and connectivity between transplanted and injured host neurons. We conclude by discussing future challenges in the field of NSC transplantation for SCI.
Section snippets
Axonal projections arising from neural stem cell grafts
There is an extensive history of CNS tissue grafting in models of SCI [2•, 3, 4]. Early studies demonstrated axonal projections from grafted tissue into host for distances as long as 4–5 mm, using both anterograde and retrograde axonal labeling techniques [3]. Intrinsic cellular markers and reporters, such as green fluorescent protein (GFP) and alkaline phosphatase (AP), may be more reliable methods for labeling axons emerging from neural implants than tracer injections. These cell-intrinsic
Connectivity and function of axons arising from neural stem cell grafts
Several studies have reported connectivity and functional recovery after grafting various types of NSCs to sites of SCI, although the strength of evidence supporting these reports varies across studies. The first study that grafted mouse ES cell-derived NSCs to a site of contusive rat SCI reported functional recovery, but provided no detailed mechanism [32•]. However, only 8% of grafted cells became neurons in this study, and there was no labeling of neuronal processes. Another study also
Axonal projection and connectivity from host neurons into neural stem cell grafts
The outgrowth and connectivity of grafted NSCs is only one component of neuronal relay formation. A complete neuronal relay also relies on ingrowth and connectivity of host axons with grafted neurons. Several studies have reported regeneration of adult host axons, including rubrospinal, reticulospinal, raphespinal, propriospinal, and sensory axons, into grafts of embryonic spinal cord tissue or ES cell-derived NSCs placed in sites of SCI [3, 4, 7••, 10, 37••, 38]. However, the distance and
Future perspectives
Axonal growth from NSCs and the potential formation of new functional neuronal relays across lesion sites offers new hope for SCI treatment. Several challenges remain. The modest growth and regeneration of adult host axons into the NSC grafts is one challenge, since the intrinsic growth capacity of adult neurons is greatly reduced [41]. Enhancing the intrinsic adult neuronal growth state [42•, 43•] or provision of neurotrophic factors in regions of lesioned axon terminals [44•] could enhance
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
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• of special interest
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•• of outstanding interest
Acknowledgements
This work was funded by grants from the Veterans Administration, NIH (NS09881), the Craig H. Neilsen Foundation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the California Institute for Regenerative Medicine.
References (47)
- et al.
Response to: Kim et al., “axon regeneration in young adult mice lacking Nogo-A/B.” Neuron 38, 187-199
Neuron
(2007) - et al.
Lineage-restricted neural precursors survive, migrate, and differentiate following transplantation into the injured adult spinal cord
Exp Neurol
(2005) - et al.
Grafted neural progenitors integrate and restore synaptic connectivity across the injured spinal cord
J Neurosci
(2011) - et al.
Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury
J Clin Invest
(2010) - et al.
Signaling in adult neurogenesis
Curr Opin Neurobiol
(2010) - et al.
Pluripotent stem cells engrafted into the normal or lesioned adult rat spinal cord are restricted to a glial lineage
Exp Neurol
(2001) - et al.
Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord
J Neurosci
(2010) - et al.
Axon outgrowth from grafts of human embryonic spinal cord in the lesioned adult rat spinal cord
Neuroreport
(1992) - et al.
Reformation of long axon pathways in adult rat central nervous system by human forebrain neuroblasts
Nature
(1990) - et al.
Integration and long distance axonal regeneration in the central nervous system from transplanted primitive neural stem cells
J Biol Chem
(2013)
Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord
Nat Med
Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation
Proc Natl Acad Sci USA
Degeneration and regeneration of the nerve system
Neural tissue grafts and repair of the injured spinal cord
Neuropathol Appl Neurobiol
Axonal projections between fetal spinal cord transplants and the adult rat spinal cord: a neuroanatomical tracing study of local interactions
J Comp Neurol
Transplants and neurotrophic factors increase regeneration and recovery of function after spinal cord injury
Prog Brain Res
Long axon growth from embryonic neurons transplanted into myelinated tracts of the adult rat spinal cord
Brain Res
Multipotent embryonic spinal cord stem cells expanded by endothelial factors and Shh/RA promote functional recovery after spinal cord injury
Exp Neurol
Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury
Exp Neurol
Long-distance growth and connectivity of neural stem cells after severe spinal cord injury
Cell
Adult neural progenitor cells provide a permissive guiding substrate for corticospinal axon growth following spinal cord injury
Eur J Neurosci
Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord
Brain
Characteristics of human fetal spinal cord grafts in the adult rat spinal cord: influences of lesion and grafting conditions
Exp Neurol
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2022, Acta BiomaterialiaCitation Excerpt :Currently, there is no effective treatment to improve neural functional recovery of patients in clinic due to the poor self-regeneration capability of damaged neurons. With in-depth development of stem cell therapy, neural stem cells (NSCs), which have the ability of self-renewal and the potential to differentiate into various nerve cells, have become an ideal candidate for SCI repair [5,6]. Unfortunately, due to the complex and adverse pathological microenvironment of SCI, the survival rate of the transplanted NSCs is very low.