MIT works toward engineered blood vessels :Vessels could be used in human body

When endothelial progenitor cells are grown on a nanopatterned substrate, they align in the direction of the pattern (right). At left are cells grown on a flat surface.
MIT scientists have found a way to induce cells to form parallel tube-like structures that could one day serve as tiny engineered blood vessels.

The researchers found that they can control the cells' development by growing them on a surface with nano-scale patterning. A paper on the work was posted this month in an online issue of Advanced Materials.

Engineered blood vessels could one day be transplanted into tissues such as the kidneys, liver, heart or any other organs that require large amounts of vascular tissue, which moves nutrients, gases and waste to and from cells.

"We are very excited about this work," said Robert Langer, MIT Institute Professor and an author of the paper. "It provides a new way to create nano-based systems with what we hope will provide a novel way to someday engineer tissues in the human body."

The work focuses on vascular tissue, which includes capillaries, the tiniest blood vessels, and is an important part of the circulatory system. The team has created a surface that can serve as a template to grow capillary tubes aligned in a specific direction.

The researchers built their template using microfabrication machinery at Draper Laboratory in Cambridge. Normally such technology is used to build micro-scale devices, but the researchers adapted it to create nano-scale patterns on a silicone elastomer substrate. The surface is patterned with ridges and grooves that guide the cells' growth.

"The cells can sense (the patterns), and they end up elongated in the direction of those grooves," said Christopher Bettinger, MIT graduate student in materials science and engineering and lead author of the paper.

The cells, known as endothelial progenitor cells (EPCs), not only elongate in the direction of the grooves, but also align themselves along the grooves. That results in a multicellular structure with defined edges, also called a band structure.

Once the band structures form, the researchers apply a commonly used gel that induces cells to form three-dimensional tubes. Unlike cells grown on a flat surface, which form a network of capillary tubes extending in random directions, cells grown on the nano-patterned surface form capillaries aligned in the direction chosen by the researchers.

The researchers believe the technique works best with EPCs because they are relatively immature cells. Earlier attempts with other types of cells, including mature epithelial cells, did not produce band structures.

Growing tissue on a patterned surface allows researchers a much greater degree of control over the results than the classic tissue engineering technique of mixing cell types with different growth factors and hoping that a useful type of tissue is produced, said Bettinger.

"With this technique, we can take the guesswork out of it," he said.

The next step is to implant capillary tubes grown in the lab into tissues of living animals and try to integrate them into the tissues.

Other authors of the paper are Jeffrey Borenstein, director of the Biomedical Engineering Center at Draper Laboratory; Zhitong Zhang, an MIT senior in the Department of Chemical Engineering; and Sharon Gerecht of Johns Hopkins University.

The research was funded by the National Institutes of Health, Draper Laboratory and the Juvenile Diabetes Research Foundation.

MIT corrects inherited retardation, autism in mice

Mark Bear, director of the Picower Institute and Picower Professor of Neuroscience (right), and Gül Dölen, a graduate student at Brown University, report the correction of fragile X syndrome in mice
Research points to potential drug treatment for humans.
Researchers at MIT's Picower Institute for Learning and Memory have corrected key symptoms of mental retardation and autism in mice.

The work, which will be reported in the Dec. 20 issue of Neuron, indicates that a certain class of drugs could have the same effect in humans. These drugs are not yet approved by the FDA, but will soon be entering into clinical trials.

Fragile X syndrome (FXS), affecting 100,000 Americans, is the most common inherited cause of mental retardation and autism. The MIT researchers corrected FXS in mice modeling the disease. "These findings have major therapeutic implications for fragile X syndrome and autism," said study lead author Mark F. Bear, director of the Picower Institute and Picower Professor of Neuroscience at MIT.

The findings support the theory that many of FXS's psychiatric and neurological symptoms--learning disabilities, autistic behavior, childhood epilepsy--stem from too much activation of one of the brain's chief network managers, the metabotropic glutamate receptor mGluR5.

"Fragile X is a disorder of excess--excess synaptic connectivity, protein synthesis, memory extinction, body growth, excitability--and remarkably, all these excesses can be reduced by reducing mGluR5," said Bear, a Howard Hughes Medical Institute investigator.

Individuals with FXS have mutations in the X chromosome's FMR1 gene, which encodes the fragile X mental retardation protein, FMRP. The MIT study found that FMRP and mGluR5 are at opposite ends of a kind of molecular seesaw. They keep each other in check and, without FMRP, mGluR5 signals run rampant.

Bear and colleagues study how genes and environment interact to refine connections in the brain. Synapses are the brain's connectors and their modifications are the basis for all learning and memory. There's a growing consensus among researchers that developmental brain disorders such as FXS, autism and schizophrenia should be considered "synapsopathies"--diseases of synaptic development and plasticity (the ability to change in response to experience).

Dendritic spines--little nubs on neurons' branchlike projections--receive many of the synaptic inputs from other neurons. Abnormal spines have long been associated with various forms of human mental retardation. In FXS, spines are more numerous, longer and more spindly than they should be. Thin spines tend to form weak connections.

The research team found that a 50 percent reduction in mGluR5 fixed multiple defects in the fragile X mice. In addition to correcting dendritic spines, reduced mGluR5 improved altered brain development and memory, restored normal body growth and reduced seizures--many of the symptoms experienced by humans with FXS.

The researchers used genetic engineering to reduce mGluR5, but a drug could accomplish the same thing. Although not yet approved by the FDA, mGluR5 blockers are entering into human clinical trials. "Insights gained by this study suggest novel therapeutic approaches, not only for fragile X but also for autism and mental retardation of unknown origin," Bear said.

Earlier this year, MIT Picower Institute researcher Susumu Tonegawa and colleagues reported positive results using a different approach to reversing FXS symptoms. Tonegawa and colleagues identified a key enzyme called p21-activated kinase, or PAK, that affects the number, size and shape of connections between neurons.

In addition to Bear, authors include Brown University graduate student Gül Dölen; Picower Institute postdoctoral fellow Emily Osterweil; B.S. Shankaranarayana Rao of the National Institute of Mental Health and Neuroscience in India; MIT graduate students Gordon B. Smith and Benjamin D. Auerbach; and Sumantra Chattarji of the National Center for Biological Sciences and Tata Institute of Fundamental Research in India.

This work is supported by the National Institute of Mental Health; the National Institute of Child Health and Human Development; the National Fragile X Foundation; FRAXA, a Fragile X research foundation; and the Simons Foundation.