The extracellular matrix fibulin 7 maintains epidermal stem cell heterogeneity during skin aging.

Tissue stem cells (SCs) divide infrequently as a protective mechanism against internal and external stresses associated with aging. Here, we demonstrate that slow- and fast-cycling SCs in the mouse skin epidermis undergo distinct aging processes. Two years of lineage tracing reveals that Dlx1+ slow-cycling clones expand into the fast-cycling SC territory, while the number of Slc1a3+ fast-cycling clones gradually declines. Transcriptome analysis further indicate that the molecular properties of each SC population are altered with age. Mice lacking fibulin 7, an extracellular matrix (ECM) protein, show early impairments resembling epidermal SC aging, such as the loss of fast-cycling clones, delayed wound healing, and increased expression of inflammation- and differentiation-related genes. Fibulin 7 interacts with structural ECM and matricellular proteins, and the overexpression of fibulin 7 in primary keratinocytes results in slower proliferation and suppresses differentiation. These results suggest that fibulin 7 plays a crucial role in maintaining tissue resilience and epidermal SC heterogeneity during skin aging.

Defining compartmentalized stem cell populations with distinct cell division dynamics in the ocular surface epithelium.

Adult tissues contain label-retaining cells (LRCs), which are relatively slow-cycling and considered to represent a property of tissue stem cells (SCs). In the ocular surface epithelium, LRCs are present in the limbus and conjunctival fornix; however, the character of these LRCs remains unclear, owing to lack of appropriate molecular markers. Using three CreER transgenic mouse lines, we demonstrate that the ocular surface epithelium accommodates spatially distinct populations with different cell division dynamics. In the limbus, long-lived Slc1a3CreER-labeled SCs either migrate centripetally toward the central cornea or slowly expand their clones laterally within the limbal region. In the central cornea, non-LRCs labeled with Dlx1CreER and K14CreER behave as short-lived progenitor cells. The conjunctival epithelium in the bulbar, fornix and palpebral compartment is regenerated by regionally unique SC populations. Severe damage to the cornea leads to the cancellation of SC compartments and conjunctivalization, whereas milder limbal injury induces a rapid increase of laterally expanding clones in the limbus. Taken together, our work defines compartmentalized multiple SC/progenitor populations of the mouse eye in homeostasis and their behavioral changes in response to injury.

Efficacy and tolerability of rosiglitazone and pioglitazone in drug-naïve Japanese patients with type 2 diabetes mellitus: a double-blind, 28 weeks' treatment, comparative study.

OBJECTIVE: A 28-week, randomized, placebo-controlled study was performed to evaluate efficacy and tolerability of rosiglitazone in Japanese type 2 diabetes patients. RESEARCH AND DESIGN METHODS: 373 patients were randomized to rosiglitazone (4-8 mg/day), pioglitazone (15-45 mg/day) or placebo. Agents were titrated to maximum doses at fixed time points in a pre-defined manner. Primary endpoints were superiority of each active treatment compared to placebo in HbA(1c) at week 16, and non-inferiority between active agents in HbA(1c) at week 28, based on a -0.45% margin. RESULTS: At week 16, improvements versus placebo were observed with rosiglitazone 4 mg/day (-0.96%, p < 0.001) and pioglitazone 30 mg/day (-1.26%, p < 0.001). At week 28, rosiglitazone and pioglitazone were associated with significant changes from baseline of -0.94% and -1.35%, respectively and rosiglitazone produced statistically and clinically significant improvement versus placebo (-1.29%, CI: -1.62, -0.97). Pioglitazone also showed significant improvement versus placebo (-1.64%, CI: -1.96, -1.31). Non-inferiority of rosiglitazone (4-8 mg/day) to pioglitazone (30-45 mg/day) was not demonstrated (treatment-difference: -0.41%, 95% CI: -0.64, -0.18). More patients treated with pioglitazone were withdrawn from the study by adverse events compared with rosiglitazone (14 vs. 4, p = 0.015). Pioglitazone was associated with higher incidences of adverse events relating to edema and weight gain compared with rosiglitazone (edema: 25.2 vs. 11.3%, weight gain: 9.4 vs. 4.4%). There were no reports of ischemic heart disease or congestive heart failure in any treatment group. CONCLUSION: Although non-inferiority to pioglitazone up to 45 mg in efficacy was not shown, rosiglitazone was confirmed to have clinically meaningful efficacy over placebo and fewer fluid-related events than pioglitazone. The study is registered on ClinicalTrials.gov as protocol NCT00297063.