You are hereDecember 5, 2016 | NSCs/NPCs
Safer iPSC-based Therapeutics: GSI Does the Job!
Review of “Pretreatment with a γ-Secretase Inhibitor Prevents Tumor-like Overgrowth in Human iPSC-Derived Transplants for Spinal Cord Injury” from Stem Cell Reports by Stuart P. Atkinson
The transplantation of neural stem and progenitor cells (NS/PCs) derived from patient-specific induced pluripotent stem cells (iPSCs) represent a promising cell-based strategy for the treatment of numerous central nervous system (CNS) disorders. However, while applications of this strategy in small and large animal models have led to motor function recovery, in some cases, graft-derived tumors can form leading to a loss of recovered motor function .
A report from Masaya Nakamura and Hideyuki Okano (Keio University School of Medicine, Tokyo, Japan) now proposes a solution to this problem: pre-treatment of cells with gamma-secretase inhibitors (GSIs) . GSIs inhibit Notch signaling in NS/PCs and promotes the shift from a stem-like proliferative state to a less proliferative differentiated state [3-5]. Knowing this, the team set out to discover if GSI treatment promoted safe and efficient NS/PC-based therapeutics for CNS disorders.
Following in vitro confirmation of GSI’s ability to suppress iPSC-NS/PC proliferation and promote differentiation into mature neural cell types, Okubo et al examined the long-term effects of GSI-treated iPSC-NS/PCs in a mouse model of spinal cord injury (SCI). This analysis employed both “dangerous” and “safe ” clones; that is, clones with and without known tumor-like overgrowth post-implantation.
Encouragingly, while GSI pretreatment of iPSC-NS/PCs led to a smaller graft volume post-transplantation when compared to the untreated control, the proportion of neurons produced increased and the functional recovery of motor skills remained. However, the mice transplanted with GSI-treated iPSC-NS/PCs exhibited no visible signs of graft-derived tumor-like overgrowth suggesting that GSI-treated cells retain their regenerative capacity and but lose the ability to overgrow.
Great news! The search now moves on to other hiPSC-derived stem and somatic cells; can we use our knowledge about signaling pathways controlling self-renewal and differentiation to select other small molecules which may promote safe and effective regenerative therapies?
- Nori S, Okada Y, Nishimura S, et al. Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition. Stem Cell Reports 2015;4:360-373.
- Okubo T, Iwanami A, Kohyama J, et al. Pretreatment with a gamma-Secretase Inhibitor Prevents Tumor-like Overgrowth in Human iPSC-Derived Transplants for Spinal Cord Injury. Stem Cell Reports 2016;7:649-663.
- Crawford TQ and Roelink H. The notch response inhibitor DAPT enhances neuronal differentiation in embryonic stem cell-derived embryoid bodies independently of sonic hedgehog signaling. Dev Dyn 2007;236:886-892.
- Nelson BR, Hartman BH, Georgi SA, et al. Transient inactivation of Notch signaling synchronizes differentiation of neural progenitor cells. Dev Biol 2007;304:479-498.
- Ogura A, Morizane A, Nakajima Y, et al. gamma-secretase inhibitors prevent overgrowth of transplanted neural progenitors derived from human-induced pluripotent stem cells. Stem Cells Dev 2013;22:374-382.