The Absence of Laminin α4 in Male Mice Results in Enhanced Energy Expenditure and Increased Beige Subcutaneous Adipose Tissue.

Laminin α4 (LAMA4) is located in the extracellular basement membrane that surrounds each individual adipocyte. Here we show that LAMA4 null (Lama4-/-) mice exhibit significantly higher energy expenditure (EE) relative to wild-type (WT) mice at room temperature and when exposed to a cold challenge, despite similar levels of food intake and locomotor activity. The Lama4-/- mice are resistant to age- and diet-induced obesity. Expression of uncoupling protein 1 is higher in subcutaneous white adipose tissue of Lama4-/- mice relative to WT animals on either a chow diet or a high-fat diet. In contrast, uncoupling protein 1 expression was not increased in brown adipose tissue. Lama4-/- mice exhibit significantly improved insulin sensitivity compared with WT mice, suggesting improved metabolic function. Overall, these data provide critical evidence for a role of the basement membrane in EE, weight gain, and systemic insulin sensitivity.

An epidemiologic perspective on the stem cell hypothesis in human carcinogenesis.

BACKGROUND: Tomasetti and Vogelstein have hypothesized that the patterns of cancer incidence in various cells and tissues are highly correlated with the estimated lifetime number of stem cell divisions. The authors reviewed the risks in tissues of 17 types of cancer from the United States and 69 additional countries. Positive correlations were observed consistently between the tissue - specific cancer incidence and the estimated lifetime number of stem cell divisions. The authors concluded that approximately two-thirds of global cancer incidence may be attributed to random DNA replication errors. METHODS: An epidemiologic perspective is presented that may serve as a counterpoint in interpreting organ-specific cancer risks. The unifying nature of the Tomasetti/Vogelstein hypothesis must be viewed in the context of diverse and contrasting global trends and patterns of types and "causes" of cancers that are closely linked with economic development and cultural lifestyle practices. The presentation is organized by reviewing the global burden of cancer; concepts of causal inferences and counterfactual assumptions; multifactorial causes of hepatocellular carcinoma and a hierarchy of causes that varies internationally; tobacco carcinogenesis and the multiplex associations with 19 cancer sites and tissues; profile in contrasts in transit through the small and large intestine. OBSERVATIONS AND CONCLUSIONS: It is readily recognized that DNA replication errors and number of stem cell divisions may vary in individuals and populations due to external environmental genotoxic chemicals and biologic agents, and internal hormonal and metabolic factors. There is a striking contrast in the risk of adenocarcinoma in the small intestine with that in the large intestine. Tomasetti and Vogelstein indicated that the cumulative number of divisions of stem cells over a lifetime in normal epithelial mucosal cells from colorectal cancer patients was 4 time greater than in the epithelial tissue from patients with adenocarcinoma of the small intestine. Their conclusion would suggest a "seed" and "soil" interaction rather than exclusively the independence of either component. Namely, that the contrasting physiological, biochemical, microbial and immunological features in the lumen and on the mucosal surface of the large intestine, in contrast to that in the small intestine, would foster molecular genetic and epigenetic events that are advantageous to neoplasia in the large intestine.

Long-term in-vivo tumorigenic assessment of human culture-expanded adipose stromal/stem cells.

After more than a decade of extensive experimentation, the promise of stem cells to revolutionize the field of medicine has negotiated their entry into clinical trial. Adipose tissue specifically holds potential as an attainable and abundant source of stem cells. Currently undergoing investigation are adipose stem cell (ASC) therapies for diabetes and critical limb ischemia, among others. In the enthusiastic pursuit of regenerative therapies, however, questions remain regarding ASC persistence and migration, and, importantly, their safety and potential for neoplasia. To date, assays of in vivo ASC activity have been limited by early end points. We hypothesized that with time, ASCs injected subcutaneously undergo removal by normal tissue turnover and homeostasis, and by the host's immune system. In this study, a high dose of culture expanded ASCs was formulated and implanted as multicellular aggregates into immunocompromised mice, which were maintained for over one year. Animals were monitored for toxicity, and surviving cells quantified at study endpoint. No difference in growth/weight or lifespan was found between cell-treated and vehicle treated animals, and no malignancies were detected in treated animals. Moreover, real-time PCR for a human specific sequence, ERV-3, detected no persistent ASCs. With the advent of clinical application, clarification of currently enigmatic stem cell properties has become imperative. Our study represents the longest duration determination of stem cell activity in vivo, and contributes strong evidence in support of the safety of adipose derived stem cell applications.