Fairfax, VA, USA. Transplanted neurons grown from embryonic stem cells can fully integrate into the brains of young animals, according to new research.

Necessary for normal behavior, healthy brains have stable and precise connections between cells. This new finding is the first to show that stem cells can be directed not only to become specific brain cells, but to link correctly.

"These stem cell-derived neurons can grow nerve fibers between the brain's cerebral cortex and the spinal cord. The study confirms the use of stem cells for therapeutic goals," said James Weimann, PhD, of Stanford Medical School.

In this study, a team of neuroscientists focused on cells that transmit information from the brain's cortex, some of which are responsible for muscle control. It is these neurons that are lost or damaged in spinal cord injuries and amyotrophic lateral sclerosis (ALS). The findings appear in The Journal of Neuroscience.

To successfully integrate new cells into a brain, the researchers first had to condition unspecialized cells to become specific cells in the brain's cortex. Cells that were precursors to cortical neurons were grown in a Petri dish until they displayed many of the same characteristics as mature neurons. The young neurons were then transplanted into the brains of newborn mice -- specifically, into regions of the cortex responsible for vision, touch, and movement.

Neuron Transplant. This is a single stem cell-derived neuron that has migrated away from the transplantation site in the cortex and grown into a mature neuron. The blue stain shows the nuclei of the endogenous neural cells in this part of the brain. Courtesy of Weimann et al. in The Journal of Neuroscience (2010).Until now, making these proper cellular connections has been a fundamental problem in nervous system transplant therapy. In this case, the maturing neurons extended to the appropriate brain structures, and, just as importantly, avoided inappropriate areas.

For example, cells transplanted into the visual cortex reached two deep brain structures called the superior colliculus and the pons, but not to the spinal cord; cells placed into the motor area of the cortex stretched into the spinal cord but avoided the colliculus.

"The authors show that appropriate connectivity for one important class of projection neurons can be obtained in newborn animals," said Mahendra Rao, MD, PhD, an expert in stem cell biology at Life Technology, who was unaffiliated with the study.

The researchers also compared two methods used to grow transplantable cells, only one of which produced the desired results. "The authors provide a protocol for how to get the right kind of neurons to show appropriate connectivity," Rao said. "It's a huge advance in the practical use of these cells."

Researchers will now explore whether the same results can be achieved in adult animals and, ultimately, humans. Weimann and his colleagues also hope to understand how the transplanted cells "knew" to connect in precisely the right way, and whether they can generate the right behaviors, such as vision and movement.

CitationMurine Embryonic Stem Cell-Derived Pyramidal Neurons Integrate into the Cerebral Cortex and Appropriately Project Axons to Subcortical Targets. Makoto Ideguchi, Theo D. Palmer, Lawrence D. Recht, and James M. Weimann. The Journal of Neuroscience 2010; 30(3): 894-904. doi:10.1523/JNEUROSCI.4318-09.2010

Abstract

Although embryonic stem (ES) cells have been induced to differentiate into diverse neuronal cell types, the production of cortical projection neurons with the correct morphology and axonal connectivity has not been demonstrated. Here, we show that in vitro patterning is critical for generating neural precursor cells (ES-NPCs) competent to form cortical pyramidal neurons. During the first week of neural induction, these ES-NPCs begin to express genes that are specific for forebrain progenitors; an additional week of differentiation produces mature neurons with many features of cortical pyramidal neurons. After transplantation into the murine cerebral cortex, these specified ES-NPCs manifest the correct dendritic and axonal connectivity for their areal location. ES-NPCs transplanted into the deep layers of the motor cortex differentiate into layer 5 pyramidal neurons and extend axons to distant subcortical targets such as the pons and as far caudal as the pyramidal decussation and descending spinal tract and, importantly, do not extend axons to inappropriate targets such as the superior colliculus (SC). ES-NPCs transplanted into the visual cortex extend axons to the dorsal aspect of the SC and pons but avoid ventral SC and the pyramidal tract, whereas cells transplanted deep into the somatosensory cortex project axons to the ventral SC, avoiding the dorsal SC. Thus, these data establish that ES-derived cortical projection neurons can integrate into anatomically relevant circuits.

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