Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury

Abstract

Various types of induced pluripotent stem (iPS) cells have been established by different methods, and each type exhibits different biological properties. Before iPS cell-based clinical applications can be initiated, detailed evaluations of the cells, including their differentiation potentials and tumorigenic activities in different contexts, should be investigated to establish their safety and effectiveness for cell transplantation therapies. Here we show the directed neural differentiation of murine iPS cells and examine their therapeutic potential in a mouse spinal cord injury (SCI) model. "Safe" iPS-derived neurospheres, which had been pre-evaluated as nontumorigenic by their transplantation into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse brain, produced electrophysiologically functional neurons, astrocytes, and oligodendrocytes in vitro. Furthermore, when the safe iPS-derived neurospheres were transplanted into the spinal cord 9 d after contusive injury, they differentiated into all three neural lineages without forming teratomas or other tumors. They also participated in remyelination and induced the axonal regrowth of host 5HT + serotonergic fibers, promoting locomotor function recovery. However, the transplantation of iPSderived neurospheres pre-evaluated as "unsafe" showed robust teratoma formation and sudden locomotor functional loss after functional recovery in the SCI model. These findings suggest that preevaluated safe iPS clone-derived neural stem/progenitor cells may be a promising cell source for transplantation therapy for SCI.neural stem/progenitor cell | cell transplantation | regenerative medicine | remyelination | axonal regrowth

Cell Therapy for Spinal Cord Injury by Neural Stem/Progenitor Cells Derived from iPS/ES Cells

“…Next, we used a mouse iPS cell clone whose safety had been confirmed (38 C2 clone), to study the effectiveness of treating SCI by transplanting neurospheres derived from it into the lesion site in a mouse model [31]. The 38 C2-iPS-derived secondary neurosphere (38 C2-SNS) transplantation was performed in the subacute stage on day 9 after the injury.…”

Cell Therapy for Multiple Sclerosis

“…Although the use of ES cells dictates an allogeneic donor cell source, the recent generation of induced pluripotential stem (iPS) cells from somatic mouse [213] cells and from human [214,215] [216][217][218] and oligodendrocytes [219,220]. It will now be necessary to explore the potential for generating populations of iPS-derived oligodendrocytes for autologous grafting in the myelin disorders.…”

Engineering personalized neural tissue by combining induced pluripotent stem cells with fibrin scaffolds

“…Another safety concern is related to the sustained proliferation of implanted cells. To address this, a protocol to evaluate non-tumor forming "safe" iPSC lines was developed for therapeutic applications [10,11]. When this screening process is used, iPSCs show a lower risk of tumour formation compared to otherwise unscreened ESCs.…”

“…Furthermore, the somatic cell type from which iPSCs are derived and choice of reprogramming factors affect the ability of the cells to differentiate into desired types [14]. However, despite the comparatively lower efficiency, these studies have shown successful differentiation of iPSCs into neural phenotypes including, neurons, astrocytes, and oligodendrocytes [11][12][13][14]. Thus, progress toward more efficient neural differentiation protocols represents an important step in the development of clinically relevant iPSC-based regenerative therapies for the diseases and disorders of the nervous system [15].…”

“…Using a neural induction protocol initiated by EB formation in the presence of RA, Miura et al [10] showed that iPSCs can differentiate into the three cell types of the central nervous system -neurons, oligodendrocytes, and astrocyteswithout teratoma formation after implantation. In a follow-up study, appropriately evaluated "safe" iPSC-derived neural progenitor cells were implanted into a mouse spinal cord injury model where they differentiated into neural lineage cells and promoted functional recovery [11]. In another study initiating neural differentiation using EB formation, iPSC-derived dopaminergic neurons were implanted into a rat Parkinson's Disease model, contributing to improved behavioural outcomes [35].…”