Grafted human-induced pluripotent stem-cell–derived neurospheres promote motor functional recovery after spinal cord injury in mice

Abstract

Once their safety is confirmed, human-induced pluripotent stem cells (hiPSCs), which do not entail ethical concerns, may become a preferred cell source for regenerative medicine. Here, we investigated the therapeutic potential of transplanting hiPSC-derived neurospheres (hiPSC-NSs) into nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice to treat spinal cord injury (SCI). For this, we used a hiPSC clone (201B7), established by transducing four reprogramming factors (Oct3/4, Sox2, Klf4, and cMyc) into adult human fibroblasts. Grafted hiPSC-NSs survived, migrated, and differentiated into the three major neural lineages (neurons, astrocytes, and oligodendrocytes) within the injured spinal cord. They showed both cell-autonomous and noncellautonomous (trophic) effects, including synapse formation between hiPSC-NS-derived neurons and host mouse neurons, expression of neurotrophic factors, angiogenesis, axonal regrowth, and increased amounts of myelin in the injured area. These positive effects resulted in significantly better functional recovery compared with vehicle-treated control animals, and the recovery persisted through the end of the observation period, 112 d post-SCI. No tumor formation was observed in the hiPSC-NS-grafted mice. These findings suggest that hiPSCs give rise to neural stem/progenitor cells that support improved function post-SCI and are a promising cell source for its treatment.stem-cell-based medicine | cell transplantation | neurotrauma | synaptic connection S tem-cell-based approaches, such as the transplantation of neural stem/progenitor cells (NS/PCs), are promising sources of therapies for various central nervous system disorders (1-3). Previous studies reported functional recovery after transplantation of NS/PCs into the injured spinal cord of rodents and nonhuman primates (4-9). Furthermore, recent studies revealed that embryonic stem cells (ESCs) can generate neural cells including NS/PCs (10-12) and oligodendrocyte precursor cells (OPCs) (13,14). Therefore, human ESC-based therapies are moving out of the laboratory and into clinical treatments for spinal cord injury (SCI) (12,13,15). However, the use of human ESC-based therapies is complicated by ethical concerns in certain countries. To avoid the problems associated with ESCs, we previously established induced pluripotent stem cells (iPSCs) from mouse fibroblasts (16, 17) and confirmed the therapeutic potential of iPSC-derived neurospheres (iPSC-NSs) for treating SCI in animal models (18).Here, aiming at human iPSC-based therapies for SCI patients, we examined the therapeutic potential of human iPSC-NSs by transplanting them into nonobese diabetic severe combined immunodeficient (NOD-SCID) SCI model mice. We used a clone from human iPSCs (hiPSCs) that we established from adult human dermal fibroblasts by the retroviral transduction of four reprogramming factors; for the clone used in this study, 201B7, the factors were Oct3/4, Sox2, Klf4, and c-Myc (19). These grafted hiPSC-NSs survived, migrated, and differentiated in...

Treatment of a Mouse Model of Spinal Cord Injury by Transplantation of Human Induced Pluripotent Stem Cell-Derived Long-Term Self-Renewing Neuroepithelial-Like Stem Cells

“…Fujimoto, Abematsu, Falk et al 1169 www.StemCells.com further improvements in the treatment of SCI [41]. However, transplantation studies of hiPS-NSCs, initially using mouse models of SCI [9], are in their infancy.…”

“…In the present study, we used NOD-SCID mice, which are a suitable model for xenograft research because they are constitutively immunodeficient; their pathology and innate immune response after SCI are also similar to those of other mouse strains [4,9,28].…”

“…Nevertheless, only recently has the efficacy of hiPS-NSC transplantation into SCI begun to be investigated [9]. To determine whether our hiPS-lt-NES cells have a therapeutic capability, we first sought to compare the effects of these cells with those of human fetal spinal cord-derived NSCs (hsp-NSCs).…”

“…Human iPSCs (hiPSCs) can be generated from cells in adult tissue, making it possible to create iPSCs from SCI patients themselves. From the viewpoint of ethics and host immune rejection, NSCs derived from human iPSCs (hiPS-NSCs) appear to be an ideal resource for transplantation therapy, and the efficacy of hiPS-NSC transplantation in SCI treatment has just begun to be investigated using the mouse model of SCI [9].…”

Cardiac Repair Using Stem Cells Conditioned Media Based Therapy in a Rodent Model of Myocardial Infarction and Heart Failure

“…One very important aspect of HiPSCs is that, they can be aimed to differentiate into a specified lineage which unlocked many opportunities for the research in regenerative medicine, therapeutic for disease modeling and drug discovery. [46][47][48][49][50][51] It carries the advantage of eliminating the ethical controversy, minimize the immune rejection and personalized approach for drug administration.…”