Migratory potential of transplanted glial progenitors as critical factor for successful translation of glia replacement therapy: The gap between mice and men

Abstract

Neurological disorders are a major threat to public health. Stem cell-based regenerative medicine is now a promising experimental paradigm for its treatment, as shown in pre-clinical animal studies. Initial attempts have been on the replacement of neuronal cells only, but glial progenitors (GPs) are now becoming strong alternative cellular therapeutic candidates to replace oligodendrocytes and astrocytes as knowledge accumulates about their important emerging role in various disease processes. There are many examples of successful therapeutic outcomes for transplanted GPs in small animal models, but clinical translation has proved to be challenging due to the 1,000-fold larger volume of the human brain compared to mice. Human GPs transplanted into the mouse brain migrate extensively and can induce global cell replacement, but a similar extent of migration in the human brain would only allow for local rather than global cell replacement. We review here the mechanisms that govern cell migration, which could potentially be exploited to enhance the migratory properties of GPs through cell engineering pre-transplantation. We furthermore discuss the (dis)advantages of the various cell delivery routes that are available, with particular emphasis on intra-arterial injection as the most suitable route for achieving global cell distribution in the larger brain. Now that therapeutic success has proven to be feasible in small animal models, future efforts will need to be directed to enhance global cell delivery and migration to make bench-to-bedside translation a reality.

Neuronal Stem Cell and Drug Interactions: A Systematic Review and Meta-Analysis: Concise Review

“…Here, we performed meta‐analyses on the effect of drugs used in the elderly and both the proliferation and differentiation of neuronal stem cells. We did not focus on drug effects on other stem cell functions such as migration and survival. The exclusion was made because migration is difficult to measure in vivo and it has different effects based on species differences . On the other hand, survival, explicitly defined, is not a function of stem cells.…”

“…We did not focus on drug effects on other stem cell functions such as migration and survival. The exclusion was made because migration is difficult to measure in vivo and it has different effects based on species differences [41].…”

Chemobrain as a Product of Growing Success in Chemotherapy - Focus On Glia As Both A Victim And A Cure

“…The success of GRPs in animal models of myelin disorders as well as models of neurodegeneration make them a very attractive therapeutic option for psychiatric disorders, particularly where the glial component might be heavily affected, such as in chemobrain. Considering the above, we would like to encourage expanding the search for mechanisms underlaying chemobrain beyond interference with neurogenesis [95]. We hypothesize that chemotherapy may interfere with the process of gliogenesis through decreasing the pool of proliferating precursors of glia.…”

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…Although the microglial field is intensively researched at present, less is still known about how microglia can be precisely targeted for optimal therapeutic efficacy. The concept of glial replacement therapy using progenitors has recently been proposed (Cartier, Lewis, Zhang, & Rossi, ; Shen, Li, Bao, & Wang, ; Srivastava, Bulte, Walczak, & Janowski, ). In this review we will introduce and discuss a new experimental paradigm to specifically control the excessive activation of microglia in vivo using fully differentiated and pre‐activated cells, and provide a rationale for its translation into clinical practice.…”