From mice to mind: Strategies and progress in translating neuroregeneration

Abstract

Decisions about what experimental therapies are advanced to clinical trials are based almost exclusively on findings in preclinical animal studies. Over the past 30 years, animal models have forecast the success of hundreds of neuroprotective pharmacological therapies for stroke, Alzheimer׳s disease, spinal cord injury, traumatic brain injury and amyotrophic lateral sclerosis. Yet almost without exception, all have failed. Rapid advances in stem cell technologies have raised new hopes that these neurological diseases may one day be treatable. Still, how can neuroregenerative therapies be translated into clinical realities if available animal models are such poor surrogates of human disease? To address this question we discuss human and rodent neurogenesis, evaluate mechanisms of action for cellular therapies and describe progress in translating neuroregeneration to date. We conclude that not only are appropriate animal models critical to the development of safe and effective therapies, but that the multiple mechanisms of stem cell-mediated therapies may be particularly well suited to the mechanistically diverse nature of central nervous system diseases in mice and man.

Radiation-induced brain injury: low-hanging fruit for neuroregeneration

“…Alternatively, OPCs, may also possess trophic and supportive functions in similar manner to NSCs, such as ability to modulate inflammation, secrete neuroprotective compounds, promote endogenous neurogenesis augment neuronal plasticity. 12,85 As such, OPC transplantation may mediate behavioral recovery via multiple synergistic actions of cell replacement, avoiding secondary cellular changes consequent to myelin and OPC loss, as well as potentially a plethora of other trophic mechanisms.…”

Current and emerging treatment options for spinal cord ischemia

“…Some potentially neuroregenerative treatments currently being studied for the treatment of traumatic spinal cord injury include chondroitinase ABC, self-assembling peptides, and rho inhibition [56]. In addition, cell-based therapies, including the use of embryonic stem cells, neural stem cells, induced pluripotent stem cells, mesenchymal stromal cells, Schwann cells, olfactory ensheathing cells, and macrophages, have shown promise in preclinical and a few clinical trials [117]. However, these trials focus on traumatic injury, and potential regenerative capacity in SCI has to be elucidated.…”

Animal Models in Translational Research: Rosetta Stone or Stumbling Block?

“…may be impossible to represent effectively in any other species. In these cases, we must seek ethical and feasible ways to study them in humans, as well as identify relevant endophenotypes, biomarkers, and constituent mechanisms that are accessible in non‐human models …”

“…The complexity of most human diseases far exceeds what any single model (however carefully constructed or evolutionarily fortuitous) can represent . Thinking in terms of a portfolio rather than merely replacing one model with another is a way to capture more diversity without sacrificing the power of well‐developed core models, which are very good at what they do − even though they alone ca not do everything.…”