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“It is remarkable how much we can learn from these three-dimensional systems,” says Shahin Rafii, an HHMI investigator at Weill Cornell Medical College who recently reported a major advance in sustaining adult stem cells in the lab. For one thing, he explains, “When you introduce a third dimension, cells turn on a whole slew of new physiologically relevant genes.” For example, in 3-D cocultures with vascular cells, stem cells start to behave like stem cells in their natural niche, initiating preset programs for self-renewal and differentiation.

A 3-D culture also recapitulates what happens in development, Rafii adds. Compared with stem cells grown on flat cultures, cells nurtured in Rafii’s 3-D environments experience a more normal physiological, biochemical, metabolic, and physical milieu in vivo, enhancing their viability for transplant.

HHMI investigators Kristi Anseth at the University of Colorado at Boulder and Sangeeta Bhatia at the Massachusetts Institute of Technology have created 3-D systems in ambitious tissue engineering projects. Bhatia’s functioning miniature livers implanted in mice bring her closer to her goal of helping patients with liver disease. Anseth is tinkering with the composition of 3-D gel matrix materials that someday might allow doctors to repair cartilage and bone defects with cell implants activated by light from outside the body. With HHMI investigator Natalie Ahn, Anseth is using 3-D cultures to learn just how cancer cells move around—and finding more surprises.

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“I think everybody now is considering whether their experimental questions might be better answered in a
3-D setting,” says Joan Brugge at Harvard Medical School.

Since the early 1990s, Brugge, a former HHMI investigator, has been studying the development of breast cancer by inserting oncogenes into “hollow cyst-like structures that resemble the milk-secreting glandular structures found in the human breast,” she says. “In 3-D, different oncogenes induced distinct architectural changes that resembled structural variations seen in different types of breast cancer.”

Noting that the microenvironment surrounding cancer cells helps determine their invasiveness—a process difficult to model in 2-D systems—oncogene pioneer Robert Weinberg at the Whitehead Institute wrote in a 2002 review, “Suddenly, the study of cancer cells in two dimensions seems quaint, if not archaic.”

An early multiuse 3-D cell culture technique came from research on the basement membrane, which underlies epithelial cells that line hollow organs. Made up of collagen and large proteins called laminins, it is a protective barrier, an anchor, and a source of signals that regulate processes such as blood vessel formation and wound healing.

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