Inducing Axons to Connect Through Scar Tissue in a Mouse Model of Spinal Injury
The two primary challenges in nerve regeneration are firstly to induce nerve tissue to regrow at all, and secondly to find a way to deal with the blockade of scarring that forms around injury sites. The existence of this scar tissue is why it is the case that some progress has been made in treatment for recent nerve injury, but very little can yet be done for patients with older injuries. In that context, the recent research results noted here are exciting, an advance that offers tangible hope to the many people who presently live with loss of function due to severed or damaged nerves. This is still very early stage work, however, and we all know that it takes long years to move from initial demonstrations in animal models to clinical trials to general availability.
Regeneration of the spinal cord has been a heavily advocated and well funded goal for as long as Fight Aging! has existed. Those us of a certain age no doubt recall the Christopher & Dana Reeve Foundation in the period in which its principals were more vocal and present in the media, in the early days of high hopes for stem cell research, and prior to Christopher Reeve's untimely death as a consequence of his spinal injury. That organization remains active, and is one amongst many supporting this line of research and development. It is a sad truth that when regulation of medicine forces a ten year or longer road from clinical readiness to clinical availability, added to the time needed to build working therapies, it is the case that the hopes of the present generation of patients only become a reality for the next generation of patients.
Researchers have identified a three-pronged treatment that triggers axons - the tiny fibers that link nerve cells and enable them to communicate - to regrow after spinal cord injury in rodents. Not only did the axons grow through scars, they could also transmit signals across the damaged tissue. "Previous studies had tested each of the three treatments separately, but never together. The combination proved to be the key."
Many decades of research have shown that a human's nerve fibers need three things to grow: genetic programming to switch on axon growth; a molecular pathway for the fibers to grab and grow along; and a trail of protein "bread crumbs" that spur the axons to grow in a particular direction. All three of these conditions are active when humans develop in the womb. After birth, these processes shut down, but the genes that control the growth programs are still sleeping in the body. The goal was to reawaken these genes and then launch the entire process anew with the three-pronged approach.
Not only had axons grown robustly through the scar tissue, but many fibers also had penetrated into the remaining spinal cord tissue on the other side of the lesion and made new connections with neurons there. When we stimulated the animal's spinal cord with a low electrical current above the injury site, the regrown axons conducted 20 percent of normal electrical activity below the lesion. In contrast, the untreated animals exhibited none. Despite the finding suggesting that the newly formed connections can conduct signals across the injury, the rodents' ability to move did not improve. "We expect that these regrown axons will behave like axons newly grown during development - they do not immediately support coordinated functions. Much like a newborn must learn to walk, axons that regrow after injury will require training and practice before they can recover function."
Required growth facilitators propel axon regeneration across complete spinal cord injury
Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after injury, but efficient reversal of this regrowth failure remains elusive. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults - (i) neuron intrinsic growth capacity, (ii) growth-supportive substrate and (iii) chemoattraction - are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents.
We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor delivered via spatially and temporally controlled release from biomaterial depots, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions.