Stem Cells Move In, Set Up Shop in Brain

For stem cell therapies to work, it is not enough for a new neuron to settle down in the brain—it must also integrate with the neural network, sending out axons and dendrites to the right places. In the January 20 issue of the Journal of Neuroscience, researchers from Stanford Medical School in Palo Alto, California, report success in getting neurons from embryonic stem cells to connect with the right host neurons in neonatal mice. The researchers, led by first author Makoto Ideguchi (since moved to Yamaguchi University School of Medicine in Japan) and principal investigator James Weimann, nudged stem cells toward cortical neuron biology before implanting them, and the environment in which the cells landed did the rest.

Other researchers have shown that embryonic stem cell-derived motor neurons can form neuromuscular junctions in adult mice (see ARF related news story and Yohn et al., 2008). In the current work, Weimann and colleagues focused on the layer 5 and 6 cortical neurons, which connect the brain to spinal cord to control muscle function. These neurons are lost in amyotrophic lateral sclerosis (Boillée et al., 2006) and spinal cord injury (Hains et al., 2003).

The transplanted cortical neuron progenitors completed differentiation and formed dendrites with spines, a hallmark of cortical neurons. They sent out hundreds of axons, too many to count, and many reached the spinal cord, the authors report. Just as importantly, transplanted cells did not send axons to inappropriate places. “Observing proper axon projection is quite an important aspect of stem cell transplantation, in order to avoid side effects from aberrant connections,” noted Allison Ebert of the University of Wisconsin in Madison, who was not involved with the study, in an e-mail to ARF.

The trick was to find a sweet spot in the differentiation process. “If they are too differentiated, they are not going to be able to interpret the information when they land,” Weimann said. “If they are not differentiated enough, they are going to form tumors.” The researchers co-cultured the stem cells with MS5 mouse stromal cells (Barberi et al., 2003), which pushed them toward a neural pathway.

“Not any generic neuron can do this,” Weimann noted. The researchers treated a separate set of stem cells with retinoic acid to cause neural differentiation (Bibel et al., 2004). Although the procedure produced “beautiful” neurons, Weimann said, they were not right for the cortex. Upon transplantation, they failed to develop dendritic spines, and sent their axons all over the place, seldom connecting to appropriate subcortical targets.

The work represents an important, but early step toward stem cell therapy. In this study the researchers used one- to three-day-old mice; in older animals, they were not able to achieve full integration of the transplanted cells. “I think there are a lot of inhibitory signals in the adult brain that keep neurons from sending out axons willy-nilly,” Weimann said. However, other researchers have shown that embryonic grafts can extend axons as far as the spinal cord in adult mice (Gaillard et al., 2007), so it seems plausible that stem cells might be able to do so, too. “The mature phenotypes and dendritic spines noted on the transplanted cells is encouraging,” Ebert wrote. “The next step would be to test functional integration.”

The other key message, Weimann said, is that just putting neurons in the brain is not enough. Therapeutic neurons must be primed to connect with the proper neighbors. For example, he suggested, in stem cell therapy for Parkinson disease, improperly connected dopaminergic neurons will produce dopamine in an unregulated manner. “You really have to understand what is happening in normal development, and try to recapitulate as much of that as possible before transplantation,” Weimann said.—Amber Dance

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References

News Citations

  1. Québec: Stem Cells in ALS Update

Paper Citations

  1. Yohn DC, Miles GB, Rafuse VF, Brownstone RM. Transplanted mouse embryonic stem-cell-derived motoneurons form functional motor units and reduce muscle atrophy. J Neurosci. 2008 Nov 19;28(47):12409-18. PubMed.
  2. Boillée S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron. 2006 Oct 5;52(1):39-59. PubMed.
  3. Hains BC, Black JA, Waxman SG. Primary cortical motor neurons undergo apoptosis after axotomizing spinal cord injury. J Comp Neurol. 2003 Jun 9;462(3):328-41. PubMed.
  4. Barberi T, Klivenyi P, Calingasan NY, Lee H, Kawamata H, Loonam K, Perrier AL, Bruses J, Rubio ME, Topf N, Tabar V, Harrison NL, Beal MF, Moore MA, Studer L. Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nat Biotechnol. 2003 Oct;21(10):1200-7. PubMed.
  5. Bibel M, Richter J, Schrenk K, Tucker KL, Staiger V, Korte M, Goetz M, Barde YA. Differentiation of mouse embryonic stem cells into a defined neuronal lineage. Nat Neurosci. 2004 Sep;7(9):1003-9. PubMed.
  6. Gaillard A, Prestoz L, Dumartin B, Cantereau A, Morel F, Roger M, Jaber M. Reestablishment of damaged adult motor pathways by grafted embryonic cortical neurons. Nat Neurosci. 2007 Oct;10(10):1294-9. PubMed.

Further Reading

Papers

  1. Santilli G, Lamorte G, Carlessi L, Ferrari D, Rota Nodari L, Binda E, Delia D, Vescovi AL, De Filippis L. Mild hypoxia enhances proliferation and multipotency of human neural stem cells. PLoS One. 2010;5(1):e8575. PubMed.
  2. Shihabuddin LS, Aubert I. Stem cell transplantation for neurometabolic and neurodegenerative diseases. Neuropharmacology. 2010 May;58(6):845-54. PubMed.
  3. Liu Y, Namba T, Liu J, Suzuki R, Shioda S, Seki T. Glial fibrillary acidic protein-expressing neural progenitors give rise to immature neurons via early intermediate progenitors expressing both glial fibrillary acidic protein and neuronal markers in the adult hippocampus. Neuroscience. 2010 Mar 10;166(1):241-51. PubMed.
  4. Hwang DY, Kim DS, Kim DW. Human ES and iPS cells as cell sources for the treatment of Parkinson's disease: current state and problems. J Cell Biochem. 2010 Feb 1;109(2):292-301. PubMed.
  5. Goldstein RS, Pomp O, Brokhman I, Ziegler L. Generation of neural crest cells and peripheral sensory neurons from human embryonic stem cells. Methods Mol Biol. 2010;584:283-300. PubMed.
  6. Yabe T, Hirahara H, Harada N, Ito N, Nagai T, Sanagi T, Yamada H. Ferulic acid induces neural progenitor cell proliferation in vitro and in vivo. Neuroscience. 2010 Jan 20;165(2):515-24. PubMed.

Primary Papers

  1. Ideguchi M, Palmer TD, Recht LD, Weimann JM. Murine embryonic stem cell-derived pyramidal neurons integrate into the cerebral cortex and appropriately project axons to subcortical targets. J Neurosci. 2010 Jan 20;30(3):894-904. PubMed.

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