We have used the pH-induced self-assembly of a peptide-amphiphile to make a nanostructured fibrous scaffold reminiscent of extracellular matrix. The design of this peptide-amphiphile allows the nanofibers to be reversibly cross-linked to enhance or decrease their structural integrity. After cross-linking, the fibers are able to direct mineralization of hydroxyapatite to form a composite material in which the crystallographic c axes of hydroxyapatite are aligned with the long axes of the fibers. This alignment is the same as that observed between collagen fibrils and hydroxyapatite crystals in bone.

http://science.sciencemag.org/content/sci/294/5547/1684.full.pdf

Self-assembly and mineralization of peptide-amphiphile nanofibers

After injury to the adult central nervous system (CNS), injured axons cannot regenerate past the lesion. In this review, we present evidence that this is due to the formation of a glial scar. Chondroitin and keratan sulphate proteoglycans are among the main inhibitory extracellular matrix molecules that are produced by reactive astrocytes in the glial scar, and they are believed to play a crucial part in regeneration failure. We will focus on this role, as well as considering the behaviour of regenerating neurons in the environment of CNS injury.

/pdf/regeneration-beyond-the-glial-scar-tnk3lt4e77.pdf

Regeneration beyond the glial scar

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140673602076031.pdf

Spinal-cord injury

Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins

, fetal central nervous system cells 3‐5 , fibroblasts expressing neurotrophin-3 (ref 6), hybridoma cells expressing inhibitory protein-blocking antibodies 7 , or olfactory nerves ensheathing glial cells 8 transplanted into the acutely injured spinal cord have produced axonal regrowth or functional benefits Transplants of rat or cat fetal spinal cord tissue into the chronically injured cord survive and integrate with the host cord, and may be associated with some functional improvements 9  In addition, rats transplanted with fetal spinal cord cells have shown improvements in some gait parameters 10 , and the delayed transplantation of fetal raphe cells can enhance reflexes 11  We transplanted neural differentiated mouse embryonic stem cells into a rat spinal cord 9 days after traumatic injury Histological analysis 2‐5 weeks later showed that transplant-derived cells survived and differentiated into astrocytes, oligodendrocytes and neurons, and migrated as far as 8 mm away from the lesion edge Furthermore, gait analysis demonstrated that transplanted rats showed hindlimb weight support and partial hindlimb coordination not found in ‘sham-operated’ controls or control rats transplanted with adult mouse neocortical cells Neural progenitors isolated from the adult central nervous system differentiate into neurons and glia after transplantation into brain 12 , and differentiate into oligodendrocytes and astrocytes after transplantation into spinal cord (F Gage, personal communication) Another source of undifferentiated cells is embryonic stem (ES) cells, genetically normal immortal cells that have been derived from several species, including mouse and human, and are capable of differentiation into neurons and astrocytes after being transplanted into the brain 13‐14

Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord.

http://labs.icb.ufmg.br/lbcd/prodabi5/homepages/hugo/Hugo/AMPc3.pdf

Spinal axon regeneration induced by elevation of cyclic AMP.

Unlike neonatal axons, mammalian adult axons do not regenerate after injury. Likewise, myelin, a major factor in preventing regeneration in the adult, inhibits regeneration from older but not younger neurons. Identification of the molecular events responsible for this developmental loss of regenerative capacity is believed key to devising strategies to encourage regeneration in adults after injury. Here, we report that the endogenous levels of the cyclic nucleotide, cAMP, are dramatically higher in young neurons in which axonal growth is promoted both by myelin in general and by a specific myelin component, myelin-associated glycoprotein (MAG), than in the same types of neurons that, when older, are inhibited by myelin-MAG. Inhibiting a downstream effector of cAMP [protein kinase A (PKA)] prevents myelin-MAG promotion from young neurons, and elevating cAMP blocks myelin-MAG inhibition of neurite outgrowth in older neurons. Importantly, developmental plasticity of spinal tract axons in neonatal rat pups in vivo is dramatically reduced by inhibition of PKA. Thus, the switch from promotion to inhibition by myelin-MAG, which marks the developmental loss of regenerative capacity, is mediated by a developmentally regulated decrease in endogenous neuronal cAMP levels.

https://www.jneurosci.org/content/jneuro/21/13/4731.full.pdf

Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate.

Neurotrophic factors increase axonal growth after spinal cord injury and transplantation in the adult rat

Little axonal regeneration occurs after spinal cord injury in adult mammals. Regrowth of mature CNS axons can be induced, however, by altering the intrinsic capacity of the neurons for growth or by providing a permissive environment at the injury site. Fetal spinal cord transplants and neurotrophins were used to influence axonal regeneration in the adult rat after complete spinal cord transection at a midthoracic level. Transplants were placed into the lesion cavity either immediately after transection (acute injury) or after a 2-4 week delay (delayed or chronic transplants), and either vehicle or neurotrophic factors were administered exogenously via an implanted minipump. Host axons grew into the transplant in all groups. Surprisingly, regeneration from supraspinal pathways and recovery of motor function were dramatically increased when transplants and neurotrophins were delayed until 2-4 weeks after transection rather than applied acutely. Axonal growth back into the spinal cord below the lesion and transplants was seen only in the presence of neurotrophic factors. Furthermore, the restoration of anatomical connections across the injury site was associated with recovery of function with animals exhibiting plantar foot placement and weight-supported stepping. These findings suggest that the opportunity for intervention after spinal cord injury may be greater than originally envisioned and that CNS neurons with long-standing injuries can reinitiate growth, leading to improvement in motor function.

https://www.jneurosci.org/content/jneuro/21/23/9334.full.pdf

Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins.

Recovery of Function after Spinal Cord Injury: Mechanisms Underlying Transplant-Mediated Recovery of Function Differ after Spinal Cord Injury in Newborn and Adult Rats

Marietta McAtee

Papers

Spinal axon regeneration induced by elevation of cyclic AMP.

Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate.

Neurotrophic factors increase axonal growth after spinal cord injury and transplantation in the adult rat

Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins.

Recovery of Function after Spinal Cord Injury: Mechanisms Underlying Transplant-Mediated Recovery of Function Differ after Spinal Cord Injury in Newborn and Adult Rats