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Jun 6, 2012

Study Overturns Tenet that Smooth Muscle Cell Dedifferentiation Leads to Vascular Disorders

  • Scientists have identified a new type of stem cell in blood vessel walls that initial studies suggest gives rise to the proliferative cells that result in the vascular remodeling and neointimal hyperplasia characteristic of vascular diseases. Until now it has been widely accepted that these features are caused by proliferative and synthetic cells derived from dedifferentiated vascular smooth muscle cells (SMCs). However, researchers at the University of California, Berkeley and Stanford University have identified previously unknown stem cells known as mutipotent vascular stem cells (MVSCs) in the tunica media of both rodent and human blood vessel walls, which they claim are the real source of the proliferative/synthetic SMCs and chondrogenic cells responsible for vascular remodeling and scar tissue formation.

    Reporting in Nature Communications, Berkeley Department of Bioengineering professor Song Li, Ph.D., and colleagues say their discovery provides a completely new perspective on the cellular changes that lead to vascular diseases such as atherosclerosis, and may springboard the development of new, more effective treatments that specifically target MVSCs. “For the first time, we are showing evidence that vascular diseases are actually a kind of stem cell disease,” professor Li claims. “This work should revolutionize therapies for vascular diseases because we now know that stem cells rather than smooth muscle cells are the correct therapeutic target.” The investigators describe their findings in a paper titled “Differentiation of multipotent vascular stem cells contributes to vascular diseases".

    The first indication that blood vessel walls might contain a new type of cell came when professor Li et al immunostained rat carotid arteries to look for cells that expressed smooth muscle alpha-actin (SMA) and smooth muscle myosin heavy chain (SM-MHC), a marker of contractile SMCs. They found that while 90% of the cells were mature, contractile SMCs (i.e., SMA+/SM-MHC+), 10% of cells, located in the tunica media, were negative for SM-MHC.

    Initial culturing experiments showed that in comparison with the mature SMCs that expressed SM-MHC, the SM-MHC- cells were smaller, expressed low levels of SMA, and were highly proliferative under suitable conditions. The SM-MHC- cells could be isolated from a number of different rat blood vessels in addition to carotid arteries. In each case the isolated SM-MHC- cells expressed stem cell markers, were cloneable, and demonstrated telomerase activity. Transplantation experiments demonstrated that Schwann cells derived from the SM-MHC- cells could even contribute to nerve axon myelination in vivo.

    It seemed that the multipotent SM-MHC- cells—which the authors termed MVSCs—and not dedifferentiated SMCs might therefore be the source of synthetic and proliferative SMCs implicated in vascular diseases. Lineage tracing negated the possibility that the MVSCs were actually derived from the dedifferentiation of mature SMCs. Rather, immunostaining, differentiation, and co-culturing experiments showed that MVSCs could differentiate into mature MVSCs. Moreover, while the MVSCs remained quiescent in undamaged blood vessels, they rapidly started proliferating in response to blood vessel injury, and differentiated into cells with a synthetic phenotype, as well as chondrogenic cells that are found in the hardened walls of diseased arteries.

    Importantly, the researchers subsequently identified the same MVSC cell type in human carotid arteries. These human MVSCs expressed the same set of markers as their rat equivalents, including Sox10, Sox17, Pax-3/7, vimentin, NFM, and S100β. As with the rat MVSCs, the human cells could be induced to differentiate into Schwann cells, neuronal cells, SMCs, chondrocytes, and adipocytes.

    “This study supports a new hypothesis that MVSC activation and differentiation, instead of SMC de-differentiation, results in the proliferative and synthetic cells in the vascular wall, and that the aberrant activation and differentiation of MVSCs may play an important role in the development of vascular diseases,” professor Li et al conclude. “The multipotential of MVSC differentiation into SMCs, chondrogenic cells, and other lineages offers a novel and reasonable explanation for the complex phenotypes of cells in the diseased vessel ... These findings may have transformative impact on vascular biology and diseases, and may lead to new therapies using MVSCs as a therapeutic target.”

     


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