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“Neural Progenitors Derived From Human Induced Pluripotent Stem Cells Survive and Differentiate Upon Transplantation into a Rat Model of Amyotrophic Lateral Sclerosis”

 

From Stem Cells Translational Medicine

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which ultimately leads to death by failure of the respiratory muscles at 3–5 years post-diagnosis (Mitchell and Borasio). Currently, there are no effective treatments or preventive strategies in humans although stem-cell-based therapies may represent a possible solution. However studies which evaluated bone marrow-derived-human mesenchymal stem cells and human umbilical cord blood cells showed little or no therapeutic benefit (Lindvall and Kokaia). Additionally, while studies have described the generation of induced pluripotent stem cells (iPSCs) from ALS patients and their differentiation into motor neurons for ALS disease modeling (Bilican et alDimos et alEgawa et al and Mitne-Neto et al), there has been no description of their fate after transplantation. To this end, researchers from the laboratory of Delphine Bohl (Institut Pasteur, Paris, France) and Roland Pochet (Université Libre de Bruxelles, Brussels, Belgium) have studied the intraparenchymal transplantation of human iPSC-derived neural progenitors (iPSC-NPs) into an ALS environment and report their successful differentiation into human mature neurons, some having motoneuronal morphologies, in the grey matter of the brain (Popescu et al).

Human iPSC-NPs were injected into ventral horns of the lumbar spinal cord of wild type (WT) and a mouse with a mutation in SOD1, which accounts for 20% of all cases of ALS (Rosen et al), and were tracked using an antibody against human mitochondria (HuMit). At day one post-injection, most HuMit-positive cells expressed NES (Nestin) suggesting that they were immature NPs. OCT4 expression was not detected in such cells suggesting that reprogramming factors were silenced and pluripotency based gene expression had not been activated. Analysis at later points found numerous HuMit-positive/NES-positive cells at day 15 in both rats, but less of these cells were evident in SOD1 rats at days 15 and 30, suggesting the more rapid loss/differentiation of NPs. Microglial and astrocytic markers (Iba1 and GFAP) peaked at day 15, and were significantly reduced at day 30. However, no dual HuMit-positive/GFAP-positive cells were observed suggesting that injected iPSC-NPs did not differentiate into astrocytes, and additional analysis found no evidence of oligodendrocyte differentiation. Immunostaining of spinal cord sections found evidence of HuMit-positive cells expressing the neuronal precursor marker doublecortin (DCX) and the mature neuronal marker MAP2 at day 30, with some MAP2 cells displaying motor neuron type morphology. At day 60, the majority of transplanted cells were HuMit-positive/MAP2-positive, suggesting neuronal maturation, and were spread in the gray matter of the spinal cord. Again, morphologically, some of these cells resembled motor neurons although immunostaining could not be used to confirm this. Final analysis demonstrated that only one of 4 SOD1 rats and none of WT rats showed evidence of tissue loss from the central area of the graft, but this was shown not to be due to iPSC-NP degeneration in the ALS environment.

Disease- and patient-specific iPSCs show great potential in the in vitro modelling of neurodegenerative diseases and also have great potential for near future therapeutic applications in diseases such as Parkinson’s disease and now potentially for ALS. Previous studies have assessed human NSCs (Yan et aland Xu et al) and human glial-restricted progenitors (Lepore et al), and now the feasibility of NP use has been demonstrated; with cells engrafting surviving and differentiating into mature neurons in the spinal cord of an ALS rat model.

References

  • Bilican B et al. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci USA 2012;109:5803–5808.
  • Dimos JT et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008;321:1218 –1221.
  • Egawa N et al. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med 2012;4:145ra104.
  • Lepore AC et al. (2011) Human glial-restricted progenitor transplantation into cervical spinal cord of the SOD1 mouse model of ALS. PLoS One 6:e25968.
  • Lindvall O, Kokaia Z. Concise review: Stem cells in human neurodegenerative disorders: Time for clinical translation? J Clin Invest 2010; 120:29–40.
  • Mitchell JD, Borasio GD. Concise review: Amyotrophic lateral sclerosis. Lancet 2007; 369:2031–2041.
  • Mitne-Neto M et al. Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. Hum Mol Genet 2011;20:3642–3652.
  • Rosen DR et al. (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62.
  • Xu L et al. (2006) Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats. Transplantation 82:865–875.
  • Yan J et al. (2006) Combined immunosuppressive agents or CD4 antibodies prolong survival of human neural stem cell grafts and improve disease outcomes in amyotrophic lateral sclerosis transgenic mice. Stem Cells 24:1976–1985.

STEM CELLS correspondent Stuart P. Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.