Finding the Stem Cell User’s Manual

packbellIn recent weeks, stem cell research has once again been drawn into a battle over political, ethical, and legal questions. Given all the controversy, it’s easy to forget that there are still many scientific questions surrounding stem cells and their potential for medical use. The ability of such cells to grow into different types of organs and tissue is exciting, but harnessing that ability has remained a challenge for scientists. Much work remains to be done in finding the control panel for pushing stem cells in a particular direction – and some of that work continues despite recent court rulings.

Mesenchymal stem cells are less controversial than their embryonic cousins because they can be harvested from adult bone marrow. But they are also more restricted in their potential, with their future limited to three destinies: bone, fat, or cartilage. Of course, those three fates alone would be very useful in medicine, with applications for orthopedic surgery, arthritis, and wound healing. So scientists are looking for the best ways to manipulate mesenchymal stem cells (MSCs) toward one of those forms.

In the laboratory of Tong-Chuan He, associate professor of surgery at the University of Chicago Medical Center, the desired outcome for mesenchymal stem cells is bone.

“Our goal is try to develop an efficient way to promote cells to making bone,” He said. “Ideally, we can create a treatment where we don’t have to use protein, deliver genes or modify cells. It can be a form of cell-based therapy.”

He and colleagues tested different growth factors from the appropriately-named bone morphogenetic protein (BMP) family on the basis of their ability to drive stem cells to become bone. The majority of research and therapy development focused on two members of the family, BMP2 and BMP7. But a 2007 study by He’s lab found that a neglected underdog, BMP9, was the real heavy hitter in pushing stem cells into a career as a bone cell.

But identifying BMP9 only gave researchers the key to bone differentiation, and it was necessary to find the lock as well. A new paper published by He’s lab last month in the Journal of Biological Chemistry, in collaboration with a team of Chinese researchers, tested out different receptors for BMP9 to determine which were critical for bone differentiation. The team tested a series of type I receptors (ALK1 through ALK7) to see which ones helped BMP9 drive MSCs – harvested from adult and embryonic mice – to become bone.

A series of experiments found that two receptors, ALK1 and ALK2, were responsible for BMP-9 activity in both adult and embryonic stem cells. Silencing either receptor caused non-differentiated MSCs to pile up and incomplete bone development while cartilage development (presumably related to other signals) proceeded without a hitch. By determining how to perturb the conversion of stem cells to bone cells, He said they fill in gaps in the user’s manual of how to exploit that process medically.

“You could make an even better BMP9 by optimizing some of the interactions between the ligand and its receptors,” He said. “You would basically be making a more active BMP9, more active than the native form.”

In the end, no external stem cells may be necessary, protecting bone repair procedures from the biggest ethical and technical obstacles surrounding stem cells. After a bone fracture, bleeding at the injury site can contain stromal cells capable of differentiation into bone, He said. An “optimized” BMP9 could enhance that process, with quicker and stronger recovery the hopeful end result. Basic science like He’s newest paper bring that idealized future of using stem cell biology closer to reality.

“It’s one of the fundamental first steps to try to understand the initial steps of the signal cascade involving BMP9,” He said. “Any further potential clinical applications will need a mechanism, and this is important part of that.”

For more on He’s research and its relevance to fighting bone cancer, see this ScienceLife post from January.

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Luo, J., Tang, M., Huang, J., He, B., Gao, J., Chen, L., Zuo, G., Zhang, W., Luo, Q., Shi, Q., Zhang, B., Bi, Y., Luo, X., Jiang, W., Su, Y., Shen, J., Kim, S., Huang, E., Gao, Y., Zhou, J., Yang, K., Luu, H., Pan, X., Haydon, R., Deng, Z., & He, T. (2010). TGF /BMP Type I Receptors ALK1 and ALK2 Are Essential for BMP9-induced Osteogenic Signaling in Mesenchymal Stem Cells Journal of Biological Chemistry, 285 (38), 29588-29598 DOI: 10.1074/jbc.m110.130518

About Rob Mitchum (526 Articles)

Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.

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