The guilty party is not the smooth muscle cells within blood vesselwalls, which for decades was thought to combine with cholesteroland fat that can clog arteries. Blocked vessels can eventually leadto heart attacks and strokes, which account for one in three deathsin the United States. Instead, a previously unknown type of stem cell — a multipotentvascular stem cell — is to blame, and it should now be the focusin the search for new treatments, the scientists report in a newstudy appearing June 6 in the journal Nature Communications . “For the first time, we are showing evidence that vasculardiseases are actually a kind of stem cell disease,” saidprincipal investigator Song Li, professor of bioengineering and aresearcher at the Berkeley Stem Cell Center. “This work shouldrevolutionize therapies for vascular diseases because we now knowthat stem cells rather than smooth muscle cells are the correcttherapeutic target.” The finding that a stem cell population contributes toartery-hardening diseases, such as atherosclerosis, provides apromising new direction for future research, the study authorssaid.
“This is groundbreaking and provocative work, as it challengesexisting dogma,” said Dr. Deepak Srivastava, who directscardiovascular and stem cell research at the Gladstone Institutesin San Francisco, and who provided some of the mouse vasculartissues used by the researchers. “Targeting the vascular stemcells rather than the existing smooth muscle in the vessel wallmight be much more effective in treating vascular disease.” It is generally accepted that the buildup of artery-blocking plaquestems from the body’s immune response to vessel damage caused bylow-density lipoproteins, the bad cholesterol many people try toeliminate from their diets. Such damage attracts legions of whiteblood cells and can spur the formation of fibrous scar tissue thataccumulates within the vessel, narrowing the blood flow. The scar tissue, known as neointima, has certain characteristics ofsmooth muscle, the dominant type of tissue in the blood vesselwall.
Because mature smooth muscle cells no longer multiply andgrow, it was theorized that in the course of the inflammatoryresponse, they revert, or de-differentiate, into an earlier statewhere they can proliferate and form matrices that contribute toplaque buildup. However, no experiments published have directly demonstrated thisde-differentiation process, so Li and his research team remainedskeptical. They turned to transgenic mice with a gene that causedtheir mature smooth muscle cells to glow green under a microscope. In analyzing the cells from cross sections of the blood vessels,they found that more than 90 percent of the cells in the bloodvessels were mature smooth muscle cells. Black Metal Keyboard
They then isolated andcultured the cells taken from the middle layer of the mouse bloodvessels. After one month of cell expansion, the researchers saw a threefoldincrease in the size of the cell nucleus and the spreading area,along with an increase in stress fibers. Notably, none of the new,proliferating cells glowed green, which meant that their lineagecould not be traced back to the mature smooth muscle cellsoriginally isolated from the blood vessels. “Not only was there a lack of green markers in the cellcultures, but we noticed that another type of cell isolated fromthe blood vessels exhibited progenitor traits for different typesof tissue, not just smooth muscle cells,” said Zhenyu Tang,co-lead author of the study and a Ph.D. student in the UCBerkeley-UCSF Graduate Program in Bioengineering. Backlit Metal Keypad Manufacturer
The other co-lead author of the study, Aijun Wang, was apost-doctoral researcher in Li’s lab. “The different phenotypes gave us the clue that stem cellswere involved,” said Wang, who is now an assistant professorand the co-director of the Surgical Bioengineering Laboratory atthe UC Davis Medical Center. “We did further tests anddetected proteins and transcriptional factors that are only foundin stem cells. No one knew that these cells existed in the bloodvessel walls because no one looked for them before.” Further experiments determined that the newly discovered vascularstem cells were multipotent, or capable of differentiating intovarious specialized cell types, including smooth muscle, nerve,cartilage, bone and fat cells. ITAC Mouse Trak
This would explain why previousstudies misidentified the cells involved in vessel clogs asde-differentiated smooth muscle cells after vascular injury. “In the later stages of vascular disease, the soft vesselsbecome hardened and more brittle,” said Li. “Previously,there was controversy about how soft tissue would become hard. Theability of stem cells to form bone or cartilage could explain thiscalcification of the blood vessels.” Other tests in the study showed that the multipotent stem cellswere dormant under normal physiological conditions. When the bloodvessel walls were damaged, the stem cells rather than the maturesmooth muscle cells became activated and started to multiply.
The researchers analyzed human carotid arteries to confirm that thesame type of multipotent vascular stem cells are found in humanblood vessels. “If your target is wrong, then your treatment can’t be veryeffective,” said Dr. Shu Chien, director of the Institute ofEngineering in Medicine at UC San Diego, and Li’s former adviser.”These new findings give us the right target and should speedup the discovery of novel treatments for vascular diseases.” Grants from the National Institutes of Health and the CaliforniaInstitute for Regenerative Medicine helped support this research.