Gli1+ Adventitial Cells Have a Critical Role in Vascular Calcification in CKD

RESEARCH HIGHLIGHTS

Nature Reviews Nephrology | Published online 26 November 2016; doi:10.1038/nrneph.2016.142

CHRONIC KIDNEY DISEASE Gli1+ adventitial cells have a critical role in vascular calcification in CKD

Vascular calcification is a major com- generate adipocytes, chondrocytes osteogenic differentiation. Genetic plication of chronic kidney disease and osteoblasts. In a model of femoral ablation of Gli1+ MSC-like cells Genetic (CKD) that increases cardiovascular artery wire injury, the researchers with diphtheria toxin before the + ablation of risk. New findings from Rafael showed that Gli1 adventitial cells onset of CKD reduced Runx2 Kramann and colleagues in Benjamin can migrate into the media and mRNA expression and completely + Gli1 MSC- Humphreys’ laboratory show that in contribute to arterial repair after abolished vascular calcification. like cells … mice, Gli1+ adventitial mesenchymal acute injury. “Approximately 50% “These findings suggest that Gli1+ completely stem cell (MSC)-like cells generate of all vascular smooth muscle cells MSCs are an important therapeutic osteoblast-like cells that drive CKD- (VSMCs) that were newly formed target,” says Kramann. abolished induced arterial calcification. “It had after wire injury to the femoral artery As Gli1 is a read-out of Shh path- vascular been hypothesized that adventitial were derived from Gli1+ progenitors,” way activation, the researchers also calcification progenitors might contribute to says Kramann. investigated the effects of stimulating vascular calcification, but our study is To assess the function of Gli1+ the SHH coreceptor Smoothened on the first inducible genetic fate-tracing progenitors during vascular calci- Gli1+ progenitors. SAG, a Smoothened experiment that actually proves this,” fication, Kramann and colleagues agonist, stimulated the proliferation says Kramann. induced CKD by performing a of Gli1+ progenitors in vitro and In previous work, Kramann and two-step subtotal nephrectomy enhanced calcification during their coworkers identified Gli1 as a specific in ApoE deficient mice with osteogenic differentiation. marker of MSCs. In this study, they tdTomato-tagged Gli1+ cells. In Finally, the researchers report that used a genetic approach to induce the these mice, which developed severe GLI1 and SHH were predominantly expression of a red fluorescent protein atherosclerosis 16 weeks after CKD expressed in the adventitia of healthy (tdTomato) in Gli1+ positive cells and induction, the number of Gli1+ human arteries, whereas they were trace their fate. “Once Gli1+ cells are cells in the media and the neo highly upregulated and localized to tagged by tdTomato, they perma- intima was markedly higher than the media, adventitia and plaques nently express this protein and give in litter-mate controls. Adventitial in the calcified arteries of deceased it to all daughter cell populations,” Gli1+ cells first differentiated patients with CKD. Kramann com- explains Kramann. towards the VSMC lineage and ments that whether this increase in Using this tracing technique to then into osteoblast-like cells, as Gli1 expression in calcified arteries is isolate Gli1+ cells, the researchers shown by Runx2 expression and due to a human progenitor popula- found that Gli1+ adventitial progeni- alkaline phosphatase activity, tion similar to that found in mice is tors are multipotent in vitro; they can two characteristic markers of not yet clear. “It will be critical to study the mechanisms that recruit Gli1+ cells from the adventitia and drive their expansion and differentiation to develop novel targeted therapeutics,” says Kramann. The researchers also plan to investigate whether a Gli1+ progenitor population exists in human arteries. Andrea Aguilar

ORIGINAL ARTICLE Kramann, R. et al. Adventitial MSC-like cells are progenitors of vascular smooth muscle cells and drive vascular calcification in chronic kidney disease. Cell Stem Cell http:// Gli1-expressing cells (red) are localized in the perivascular zone in control animals (left) and generate dx.doi.org/10.1016/j.stem.2016.08.001 (2016) α-SMA+ vascular smooth muscle cells (green) after wire injury (right). Image courtesy of R. Kramann.