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It's All About Networking

Human embryonic stem cells form new circuits in rodent brains.

Having studied how human embryonic stem cells behave in a foreign nervous system — that of a rodent brain — Johns Hopkins researchers published evidence in July 2009 showing that they can become nerve cells that do indeed reach out and touch — extending their axons and ultimately snapping synapses with their new neighbors in order to create networks. 

Vassilis E. Koliatsos, M.D., an associate professor of Pathology (Neuropathology), Neurology and Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine.

“Human stem cells are capable of forming new circuits in the nervous system, a place where repairs can’t happen unless you fix circuits,” says Vassilis E. Koliatsos, M.D., an associate professor of Pathology (Neuropathology), Neurology and Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine. 

The discovery that human stem cells “differentiate beautifully” and make circuits with other nerve cells in the rat brain paves the way for transplanting human neural stem cells into rodent species in order to study a range of diseases and screen for potential drug targets.

Using cells from human blastocysts that can make almost every tissue in body, the researchers coaxed them with a protein called noggin to proceed down the pathway to becoming neurons. At precisely the right moment — when the cells were still in the process of becoming , but before they had committed to neuron-hood, as mature cells die when transplanted — the researchers grafted between 10,000 and 20,000 “wannabe” neurons into the forebrains of rats. Then they examined the rodents’ brains — some after one month, and others after two months, three months and six months.  

Human blastocyst, day 5 Human blastocyst, day 5.

“You start seeing these cells beginning to send their axons in a particular direction quite early, within the first month,” Koliatsos says. “But it does take close to six months for them to form synapses and close the circuit, which tells you they take their time.  And I’m not sure if it’s rat time or human time.”

In addition to time, distance is another contrast between networking neurons in rats as opposed to humans. Because rat brains are so much smaller, the neural pathways in the rat brain range from just a few millimeters to just over a centimeter long.  In the human brain, pathways extend for 10 to 20 centimeters or more, especially those that sustain uniquely human functions like upright gait, memory, emotion and personality. 

“When extrapolating from rat to human, the question is probably not so much if human embryonic stem cells transplanted into human brains will behave differently,” Koliatsos says.  “I’d guess that they would differentiate and behave in a similar fashion, but it’s probably going to take them much longer. I don’t know how long is too long in this context; the longer the time it takes, the greater the chances the cells would die or form tumors, and networks would not form.”

Armed with evidence that these cells do, in fact, have the capacity to form networks, his next mission is to figure out exactly how they engage with each other:  “Now we’ll start looking at the rules of the game,” he promises.

--Maryalice Yakutchik