Robert A.J. Signer

The ageing immune system: is it ever too old to become young again?

Ageing is accompanied by a decline in the function of the immune system, which increases susceptibility to infections and can decrease the quality of life. The ability to rejuvenate the ageing immune system would therefore be beneficial for elderly individuals and would decrease health-care costs for society. But is the immune system ever too old to become young again? We review here the promise of various approaches to rejuvenate the function of the immune system in the rapidly growing ageing population.

Mechanisms that Regulate Stem Cell Aging and Life Span

Mammalian aging is associated with reduced tissue regeneration, increased degenerative disease, and cancer. Because stem cells regenerate many adult tissues and contribute to the development of cancer by accumulating mutations, age-related changes in stem cells likely contribute to age-related morbidity. Consistent with this, stem cell function declines with age in numerous tissues as a result of gate-keeping tumor suppressor expression, DNA damage, changes in cellular physiology, and environmental changes in tissues. It remains unknown whether declines in stem cell function during aging influence organismal longevity. However, mechanisms that influence longevity also modulate age-related morbidity, partly through effects on stem cells.

Haematopoietic stem cells require a highly regulated protein synthesis rate

Many aspects of cellular physiology remain unstudied in somatic stem cells, for example, there are almost no data on protein synthesis in any somatic stem cell. Here we set out to compare protein synthesis in haematopoietic stem cells (HSCs) and restricted haematopoietic progenitors. We found that the amount of protein synthesized per hour in HSCs in vivo was lower than in most other haematopoietic cells, even if we controlled for differences in cell cycle status or forced HSCs to undergo self-renewing divisions. Reduced ribosome function in Rpl24Bst/+ mice further reduced protein synthesis in HSCs and impaired HSC function. Pten deletion increased protein synthesis in HSCs but also reduced HSC function. Rpl24Bst/+ cell-autonomously rescued the effects of Pten deletion in HSCs; blocking the increase in protein synthesis, restoring HSC function, and delaying leukaemogenesis. Pten deficiency thus depletes HSCs and promotes leukaemia partly by increasing protein synthesis. Either increased or decreased protein synthesis impairs HSC function.

Aging and cancer resistance in lymphoid progenitors are linked processes conferred by p16Ink4a and Arf

Lymphoid progenitors exhibit severe growth defects during aging while myelopoiesis is relatively unperturbed. These effects are due in part to the preferential expression of p16(Ink4a) and Arf in aged lymphoid progenitors. Their increased expression contributes to reduced growth and survival of lymphoid progenitors and makes them refractory to malignant transformation. Down-regulation of p16(Ink4a) and Arf in aged lymphoid progenitors reverted the senescent phenotype and restored susceptibility to transformation. These data provide a molecular explanation for the preferential effects of aging on lymphopoiesis, suggest that inhibiting p16(Ink4a) and Arf expression can rejuvenate B lymphopoiesis, and link aging and cancer resistance.

Prospective identification of functionally distinct stem cells and neurosphere-initiating cells in adult mouse forebrain

Neurosphere formation is commonly used as a surrogate for neural stem cell (NSC) function but the relationship between neurosphere-initiating cells (NICs) and NSCs remains unclear. We prospectively identified, and isolated by flow cytometry, adult mouse lateral ventricle subventricular zone (SVZ) NICs as GlastmidEGFRhighPlexinB2highCD24−/lowO4/PSA-NCAM−/lowTer119/CD45− (GEPCOT) cells. They were highly mitotic and short-lived in vivo based on fate-mapping with Ascl1CreERT2 and Dlx1CreERT2. In contrast, pre-GEPCOT cells were quiescent, expressed higher Glast, and lower EGFR and PlexinB2. Pre-GEPCOT cells could not form neurospheres but expressed the stem cell markers Slc1a3-CreERT, GFAP-CreERT2, Sox2CreERT2, and Gli1CreERT2 and were long-lived in vivo. While GEPCOT NICs were ablated by temozolomide, pre-GEPCOT cells survived and repopulated the SVZ. Conditional deletion of the Bmi-1 polycomb protein depleted pre-GEPCOT and GEPCOT cells, though pre-GEPCOT cells were more dependent upon Bmi-1 for Cdkn2a (p16Ink4a) repression. Our data distinguish quiescent NSCs from NICs and make it possible to study their properties in vivo. DOI: http://dx.doi.org/10.7554/eLife.02669.001

Lens regeneration using endogenous stem cells with gain of visual function

The repair and regeneration of tissues using endogenous stem cells represents an ultimate goal in regenerative medicine. To our knowledge, human lens regeneration has not yet been demonstrated. Currently, the only treatment for cataracts, the leading cause of blindness worldwide, is to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure poses notable risks of complications. Here we isolate lens epithelial stem/progenitor cells (LECs) in mammals and show that Pax6 and Bmi1 are required for LEC renewal. We design a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Our method differs conceptually from current practice, as it preserves endogenous LECs and their natural environment maximally, and regenerates lenses with visual function. Our approach demonstrates a novel treatment strategy for cataracts and provides a new paradigm for tissue regeneration using endogenous stem cells.

Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a

Involution of the thymus results in reduced production of naive T cells, and this in turn is thought to contribute to impaired immunity in the elderly. Early T-cell progenitors (ETPs), the most immature intrathymic T-cell precursors, harvested from the involuted thymus exhibit a diminished proliferative potential and increased rate of apoptosis and as a result their number is significantly reduced. In the present study, we show that these age-induced alterations result in part from increased expression of the Ink4a tumor-suppressor gene in ETPs. We also show that repression of Ink4a in aged ETPs results in their partial rejuvenation and that this can be accomplished by in vivo fibroblast growth factor 7 administration. These results define a genetic basis for thymocyte progenitor aging and demonstrate that the senescence-associated gene Ink4a can be pharmacologically repressed in ETPs to partially reverse the effects of aging.

Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration

Mammals have partially lost the extensive regenerative capabilities of some vertebrates, possibly as a result of chromatin-remodeling mechanisms that enforce terminal differentiation. Here, we show that deleting the SWI/SNF component Arid1a substantially improves mammalian regeneration. Arid1a expression is suppressed in regenerating tissues, and genetic deletion of Arid1a increases tissue repair following an array of injuries. Arid1a deficiency in the liver increases proliferation, reduces tissue damage and fibrosis, and improves organ function following surgical resection and chemical injuries. Hepatocyte-specific deletion is also sufficient to increase proliferation and regeneration without excessive overgrowth, and global Arid1a disruption potentiates soft tissue healing in the ear. We show that Arid1a loss reprograms chromatin to restrict promoter access by transcription factors such as C/ebpα, which enforces differentiation, and E2F4, which suppresses cell-cycle re-entry. Thus, epigenetic reprogramming mediated by deletion of a single gene improves mammalian regeneration and suggests strategies to promote tissue repair after injury.

Aging, B lymphopoiesis, and patterns of leukemogenesis

The production of B lymphocytes begins to decline steadily early in adult life and is severely compromised in the elderly. This occurrence has been attributed to intrinsic defects in early hematopoietic progenitors and B cell precursors as well as to microenvironmental changes in aged bone marrow. The aim of this review is to present an overview of B lymphocyte senescence and its underlying causes and to discuss its impact on immune function and leukemogenesis in aged individuals.

The rate of protein synthesis in hematopoietic stem cells is limited partly by 4E-BPs

Adult stem cells must limit their rate of protein synthesis, but the underlying mechanisms remain largely unexplored. Differences in protein synthesis among hematopoietic stem cells (HSCs) and progenitor cells did not correlate with differences in proteasome activity, total RNA content, mRNA content, or cell division rate. However, adult HSCs had more hypophosphorylated eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and 4E-BP2 as compared with most other hematopoietic progenitors. Deficiency for 4E-BP1 and 4E-BP2 significantly increased global protein synthesis in HSCs, but not in other hematopoietic progenitors, and impaired their reconstituting activity, identifying a mechanism that promotes HSC maintenance by attenuating protein synthesis.