Neural Stem Cell Engraftment and Myelination in the Human Brain

Abstract

Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy caused by mutation of the proteolipid protein 1 gene. Defective oligodendrocytes in PMD fail to myelinate axons, causing global neurological dysfunction. Human central nervous system stem cells (HuCNS-SCs) can develop into oligodendrocytes and confer structurally normal myelin when transplanted into a hypomyelinating mouse model. A 1-year open-label phase 1 study was undertaken to evaluate safety and to detect evidence of myelin formation after HuCNS-SC transplantation. Allogeneic HuCNS-SCs were surgically implanted into the frontal lobe white matter in four male subjects with an early-onset severe form of PMD. Immunosuppression was administered for 9 months. Serial neurological evaluations, developmental assessments, and cranial magnetic resonance imaging (MRI) and MR spectroscopy, including high-angular resolution diffusion tensor imaging (DTI), were performed at baseline and after transplantation. The neurosurgical procedure, immunosuppression regimen, and HuCNS-SC transplantation were well tolerated. Modest gains in neurological function were observed in three of the four subjects. No clinical or radiological adverse effects were directly attributed to the donor cells. Reduced T1 and T2 relaxation times were observed in the regions of transplantation 9 months after the procedure in the three subjects. Normalized DTI showed increasing fractional anisotropy and reduced radial diffusivity, consistent with myelination, in the region of transplantation compared to control white matter regions remote to the transplant sites. These phase 1 findings indicate a favorable safety profile for HuCNS-SCs in subjects with PMD. The MRI results suggest durable cell engraftment and donor-derived myelin in the transplanted host white matter.

Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells

“…Pharmacological agents aimed at modulating Piezo1 activity may be useful in directing the fate of transplanted neural stem cells toward the desired lineage. transplantation into the central nervous system (24) and currently are in clinical trials for multiple neurological conditions (25,26).…”

In vitro myelin formation using embryonic stem cells

“…Additionally, these symptoms are aggravated by inadequate myelin repair. Therefore, transplantation of exogenous cells and mobilization and recruitment of endogenous cells have been proposed as therapeutic approaches to restore myelin (Cummings et al, 2005;Gupta et al, 2012;Miron et al, 2011;Peru et al, 2008;Potter et al, 2011;Tsuji et al, 2010). For successful outcomes, it is essential to establish and maintain both stimulating and permissive cues for myelination.…”

Fetal stem cell transplantation: Past, present, and future

“…Using CNS stem cells, the company is currently developing stem cell products for use in patients with SCI, macular degeneration, and Pelizaeus-Merzbacher disease. In most cases, de novo neurogenesis is not the goal, but rather the treatment of enzyme deficiencies, as well as remyelination, or the modulation of endogenous repair via neoangiogenesis and/or neuroprotection [131][132][133][134] . Moreover, the company has isolated fetal liver progenitor cells and developed a unique co-culture system with endothelial cells in a threedimensional matrix [135] .…”