Human iPSC for Therapeutic Approaches to the Nervous System: Present and Future Applications

Abstract

Many central nervous system (CNS) diseases including stroke, spinal cord injury (SCI), and brain tumors are a significant cause of worldwide morbidity/mortality and yet do not have satisfying treatments. Cell-based therapy to restore lost function or to carry new therapeutic genes is a promising new therapeutic approach, particularly after human iPSCs became available. However, efficient generation of footprint-free and xeno-free human iPSC is a prerequisite for their clinical use. In this paper, we will first summarize the current methodology to obtain footprint- and xeno-free human iPSC. We will then review the current iPSC applications in therapeutic approaches for CNS regeneration and their use as vectors to carry proapoptotic genes for brain tumors and review their applications for modelling of neurological diseases and formulating new therapeutic approaches. Available results will be summarized and compared. Finally, we will discuss current limitations precluding iPSC from being used on large scale for clinical applications and provide an overview of future areas of improvement. In conclusion, significant progress has occurred in deriving iPSC suitable for clinical use in the field of neurological diseases. Current efforts to overcome technical challenges, including reducing labour and cost, will hopefully expedite the integration of this technology in the clinical setting.

Figure 1

Diagrammatic representation of methods used to obtain human iPSC. Different somatic cells can be used for reprogramming (left column). Reprogramming techniques (center column) first used viral based genomic integration (a) and then used footprint-free techniques (b). Footprint-free iPSC induction can be obtained by Sendai virus (b(i)); episome (b(ii)); mRNA (b(iii)); siRNA (b(iv)). Finally, culturing conditions (right column) at first requiring feeder cells evolved to xeno-free conditions to allow safer clinical translation.

Figure 2

Human iPSC can be differentiated into all cell lineages.

Figure 3

Microphotographs of footprint-free iPSC-derived astrocytes. (a) Phase contrast and (b) immunocytochemistry for GFAP 9 days after MACS sorting of mRNA iPSC-derived astrocytes.

Figure 4

Personalized medicine using patient-specific iPSC. Diagrammatic summary of reprogramming patient-specific cells into footprint-free hiPSC, engineering their DNA to carry proapoptotic genes, differentiating them into astrocytes, and reimplanting them at the time of surgery for brain tumor recurrence. (a) Dermal fibroblast cells obtained from patient. (b) Ribonucleic acid (RNA) added to cells, which turns them into stem cells. (c) Tumor cells killer gene added to stem cells. (d) Engineered cells cloned. (e) Engineered cells transformed to brain cells, astrocytes, and implanted back in the same patient at the time of surgical resection for recurrent tumor.