Translating Stem Cell Studies to the Clinic for CNS Repair: Current State of the Art and the Need for a Rosetta Stone

Abstract

Since their discovery twenty years ago and prospective isolation a decade later, neural stem cells (NSCs), their progenitors, and differentiated cell derivatives along with other stem-cell based strategies have advanced steadily toward clinical trials, spurred by the immense need to find reparative therapeutics for central nervous system (CNS) diseases and injury. Current phase I/II trials using stem cells in the CNS are the vanguard for the widely anticipated next generation of regenerative therapies and as such are pioneering the stem cell therapy process. While translation has typically been the purview of industry, academic researchers are increasingly driven to bring their findings toward treatments and face challenges in knowledge gap and resource access that are accentuated by the unique financial, manufacturing, scientific, and regulatory aspects of cell therapy. Solutions are envisioned that both address the significant unmet medical need and lead to increased funding for basic and translational research.

Direct isolation and RNA-seq reveal environment-dependent properties of engrafted neural stem/progenitor cells

“…Although engrafted NSPCs could facilitate functional recovery after SCI through multiple mechanisms 4,5,8 , our results revealed that neuroprotective effect is most significant for acute phase of SCI. Furthermore, we directly confirmed the neurohumoral secretion of engrafted NSPCs and demonstrated their secretory activities to be mostly enhanced after transplantation.…”

“…Furthermore, using BLI, we demonstrated the presence of an appropriate range in the number of transplanting cells for SCI. In clinical trials, the transplantation protocols are completely different and, in particular, the number of transplanted cells varies considerably, which is also true in animal studies 5,7,8 . This hampers the establishment of an optimal treatment for SCI.…”

“…Therefore, the transplantation of stem cells such as neural stem/progenitor cells (NSPCs) is an exciting therapeutic option for replacing damaged neural cells and inducing functional recovery [3][4][5][6] , and some clinical trials have been performed 7,8 . However, the efficacy of NSPCs for treating SCI is currently insufficient, and unexpected serious side effects have been observed following NSPC transplantation 4,7,9 .…”

“…More importantly, no direct analysis has ever been performed on the in vivo profile of NSPCs engrafted in injured spinal cord and thus the in vivo properties of engrafted cells still remain unclear. Therefore, the cellular mechanisms underlying functional improvement, the risk of tumorigenesis after transplantation and optimal transplantation protocols remains largely elusive 4,8 . Without assessing biological and molecular properties of engrafted cells in pathological environments, the development of effective and safe strategies for stem cell-based therapies cannot be possible.…”

Cell-Based Therapy for Neural Disorders — Anticipating Challenges

“…Aboody et al [10] provides an excellent review of ongoing clinical trials using stem cell-mediated approaches in the CNS (see Table 3). Although it is impossible to discuss each disease model in detail, certain generalizations are possible.…”