Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity.

Several cell populations have been reported to possess intestinal stem cell (ISC) activity during homeostasis and injury-induced regeneration. Here, we explored inter-relationships between putative mouse ISC populations by comparative RNA-sequencing (RNA-seq). The transcriptomes of multiple cycling ISC populations closely resembled Lgr5+ ISCs, the most well-defined ISC pool, but Bmi1-GFP+ cells were distinct and enriched for enteroendocrine (EE) markers, including Prox1. Prox1-GFP+ cells exhibited sustained clonogenic growth in vitro, and lineage-tracing of Prox1+ cells revealed long-lived clones during homeostasis and after radiation-induced injury in vivo. Single-cell mRNA-seq revealed two subsets of Prox1-GFP+ cells, one of which resembled mature EE cells while the other displayed low-level EE gene expression but co-expressed tuft cell markers, Lgr5 and Ascl2, reminiscent of label-retaining secretory progenitors. Our data suggest that the EE lineage, including mature EE cells, comprises a reservoir of homeostatic and injury-inducible ISCs, extending our understanding of cellular plasticity and stemness.

Bone cell precursors and the pathophysiology of bone loss.

In health, changes in bone formation and degradation rates are coupled and adequate cellular resources are available in the bone so that a change in bone formation rate occurs with an opposing change in resorption. On the other hand, the regulation of bone volume, particularly in pathological conditions, is dependent not only on the pathways that mediate terminal pathways of bone cell differentiation, but also on the availability of stem cells for allowing the differentiation to occur. Regulation of cell numbers in stem cell compartments and release of stem cells for differentiation of osteoblast or osteoclast precursors are not well understood, although it is clear that changes in stem cell numbers underlie pathological changes in bone mass. This may include effects of aging, fracture, metastatic disease, and autoimmune diseases on the precursor cell pools available for bone formation and degradation. Increases in osteoclast precursors or decreases in osteoblast precursors are common features of bone-losing states; increases in precursors may conversely occur during growth or repair processes. Rational therapy based on modifying stem cell populations may, when the processes are better understood, help prevent chronic bone-losing states and may also be of use in preventing or treating aplastic anemia and related conditions.

Developing a research agenda in biogerontology: physiological systems.

The Biology of Aging Program (BAP) at the National Institute on Aging supports research in many areas, including processes of cell senescence and apoptosis, genetic influences on aging, and how aging leads to tissue dysfunction. Several approaches to research on aging physiological systems are described, along with BAP programmatic efforts to enhance and support that research. Understanding the relation between aging and tissue dysfunction has led to new insights into how health can be improved for aged individuals.

Meeting report--National Institute on Aging Workshop on the Comparative Biology of Aging.

This Perspective is a summary of the Comparative Biology of Aging Workshop that was held in February 2002 by the National Institute on Aging in Bethesda, MD. Participants discussed ways to exploit similarities and differences in aging among diverse species to learn more about critical factors that affect aging and regulate life expectancy in animals. The aim of the workshop was to stimulate new approaches to understanding the molecular bases for differences in aging rates and life expectancy among species.

Aging bone and cartilage: cross-cutting issues.

Aging is a major risk factor for osteoarthritis and osteoporosis. Yet, these are not necessary outcomes of aging, and the relationship between age-related changes in bone and cartilage and development of disease is not clear. There are some well-described cellular changes associated with aging in multiple tissues that appear to be fundamental to the decline in function of cartilage and bone. A better understanding of age-related changes in cells and tissues is necessary to mitigate or, hopefully, avoid loss of bone and cartilage with aging. In addition, a better understanding of the dynamics of tissue maintenance in vivo is critical to developing tissue replacement and repair therapies. The role of stem cells in this process, and why tissues are not well maintained with advancing age, are frontiers for future aging research.