Stem cells can sort mitochondria by age: The renewal of tissues in aging organisms requires stem cells, which have the unusual ability to divide asymmetrically into one daughter cell that retains stem cell properties and another that differentiates into a particular tissue type. Katajisto et al. used photoactivated marker proteins to monitor the age of cell organelles in stemlike cells from human breast tissue and their distribution into daughter cells. Most organelles were evenly distributed, but daughter cells that maintained stem-cell properties received more newly produced mitochondria and fewer old ones. Science , this issue p. 340

In adults, the growth of blood vessels, a process known as angiogenesis, is essential for organ growth and repair. In many disorders including cancer, angiogenesis becomes excessive. The cellular origin of new vascular endothelial cells (ECs) during blood vessel growth in angiogenic situations has remained unknown. Here, we provide evidence for adult vascular endothelial stem cells (VESCs) that reside in the blood vessel wall endothelium. VESCs constitute a small subpopulation within CD117+ (c-kit+) ECs capable of undergoing clonal expansion while other ECs have a very limited proliferative capacity. Isolated VESCs can produce tens of millions of endothelial daughter cells in vitro. A single transplanted c-kit-expressing VESC by the phenotype lin−CD31+CD105+Sca1+CD117+ can generate in vivo functional blood vessels that connect to host circulation. VESCs also have long-term self-renewal capacity, a defining functional property of adult stem cells. To provide functional verification on the role of c-kit in VESCs, we show that a genetic deficit in endothelial c-kit expression markedly decreases total colony-forming VESCs. In vivo, c-kit expression deficit resulted in impaired EC proliferation and angiogenesis and retardation of tumor growth. Isolated VESCs could be used in cell-based therapies for cardiovascular repair to restore tissue vascularization after ischemic events. VESCs also provide a novel cellular target to block pathological angiogenesis and cancer growth. Angiogenesis—the growth of blood vessels—is essential for organ growth and repair, but also occurs during tumorigenesis and in certain inflammatory disorders. All blood vessels are lined by endothelial cells (ECs)—thin, flattened cells that form a continuous monolayer throughout the entire circulatory system. The cellular origin of new vascular ECs during blood vessel growth in angiogenic situations in adults is a matter of debate. New ECs could develop, in principle, from as yet undiscovered stem cells, as is well documented for the differentiated cells of skin or epithelia, or by the duplication of existing differentiated ECs. Here, we provide evidence for the existence of vascular endothelial stem cells (VESCs) that reside in the adult blood vessel wall endothelium. VESCs constitute a small subpopulation of ECs capable of clonal expansion, while other ECs have a very limited proliferative capacity. When isolated, these VESCs can produce tens of millions of endothelial daughter cells, and a single transplanted VESC can generate in vivo functional blood vessels that connect to host blood circulation. Isolated VESCs could be used in cell-based therapies for cardiovascular repair to restore tissue vascularization following ischemia and could also be pursued as a novel cellular target of inhibition to block pathological angiogenesis, for example during tumor growth.

Germline mutations in the gene encoding tumor suppressor kinase LKB1 lead to gastrointestinal tumorigenesis in Peutz-Jeghers syndrome (PJS) patients and mouse models; however, the cell types and signaling pathways underlying tumor formation are unknown. Here, we demonstrated that mesenchymal progenitor- or stromal fibroblast–specific deletion of Lkb1 results in fully penetrant polyposis in mice. Lineage tracing and immunohistochemical analyses revealed clonal expansion of Lkb1-deficient myofibroblast-like cell foci in the tumor stroma. Loss of Lkb1 in stromal cells was associated with induction of an inflammatory program including IL-11 production and activation of the JAK/STAT3 pathway in tumor epithelia concomitant with proliferation. Importantly, treatment of LKB1-defcient mice with the JAK1/2 inhibitor ruxolitinib dramatically decreased polyposis. These data indicate that IL-11–mediated induction of JAK/STAT3 is critical in gastrointestinal tumorigenesis following Lkb1 mutations and suggest that targeting this pathway has therapeutic potential in Peutz-Jeghers syndrome.

Niche-derived factors regulate tissue stem cells, but apart from the mechanosensory pathways, the effect of niche geometry is not well understood. We used organoids and bioengineered tissue culture platforms to demonstrate that the conical shape of Lgr5 ⁺ small intestinal stem cells (ISCs) facilitate their self-renewal and function. Inhibition of non-muscle myosin II (NM II)–driven apical constriction altered ISC shape and reduced niche curvature and stem cell capacity. Niche curvature is decreased in aged mice, suggesting that suboptimal interactions between old ISCs and their niche develop with age. We show that activation of NM IIC or physical restriction to young topology improves in vitro regeneration by old epithelium. We propose that the increase in lateral surface area of ISCs induced by apical constriction promotes interactions between neighboring cells, and the curved topology of the intestinal niche has evolved to maximize signaling between ISCs and neighboring cells.