Regenerative Medicine: iPSC immunogenicity

Induced pluripotent stem cells (iPSCs), which are reprogrammed from adult cells, have been hailed as an exciting alternative to embryonic stem cells (ESCs) for regenerative medicine. However, recent epigenetic profiling studies have raised concerns about how similar ESCs and iPSCs are, and a new study by Tongbiao Zhao et al. (Nature doi:10.1038/nature10135) shows that iPSCs can trigger an immune reaction in mice.

The gold standard assay for pluripotency involves seeing whether stem cells can form teratomas when introduced into mice. Using this system, Zhao et al. observed teratoma formation when ESCs were injected into hosts of the same genetic background; by contrast, host-matched iPSCs failed to form teratomas or formed teratomas that were subsequently immune rejected. The authors then identified a set of genes that were overexpressed in iPSC teratomas compared with ESC teratomas, and showed that overexpression of two of these genes, Zg16 and Hormad1, led to immune targeting of teratomas.

These findings raise several issues for the further investigation of iPSCs and their derivatives. Zhao et al. used iPSCs reprogrammed from ESCs, so it will be interesting to see whether iPSCs derived from adult cells and differentiated iPSCs will also be immunogenic. Furthermore, depending on the reprogramming method, the authors observed different levels of immune rejection, suggesting that the method of reprogramming might be modulated to influence the immune outcome. —MS

Infection: Parasite protection

Goblet cells in the intestine secrete a thick mucus layer comprised of mucin glycoproteins, which provides a protective barrier from pathogenic nematodes. Recent findings highlight the role of specific mucins in promoting worm expulsion.

David Thornton and his colleagues (J. Exp. Med. 208, 893–900) report that the mucin Muc5ac is upregulated in the cecum of mice infected with Trichuris muris, a model of human infection with Trichuris trichiura. Mice deficient in this mucin are incapable of expelling worms and remain susceptible to chronic infection. Aside from altering the viscous properties of the mucus, the human equivalent, MUC5AC, directly reduces nematode vitality in vitro.

These findings dovetail with recent findings (Gastroenterology 138, 1763–771) that mice deficient in Muc2, the major mucin produced in the intestine, upregulate Muc5ac with T. muris infection. Expulsion of worms is delayed (but not abolished) in Muc2-deficient mice, highlighting the roles of both mucins in host defense against nematode infection. —KDS

Metabolism: Friendly bacteria

Bacterially produced butyrate regulates energy production and cell survival in the intestine, according to a study by Dallas Donohoe et al. (Cell Metab. 13, 517–526).

Donohoe et al. investigated whether energy homeostasis in colon cells was different between control and germ-free mice. They found that NADH/NAD+ ratios and ATP levels were lower in the colon of germ-free mice and that colonocytes from these mice could undergo autophagy as a result of this energetic deficit.

These differences correlated with expression changes in genes that participate in butyrate metabolism, leading the authors to test the involvement of this metabolite in the energy deficiency they saw. Colonization of the gut of germ-free mice with bacteria from control mice or even with a single butyrate-producing bacterial species reversed the energy imbalance and prevented autophagy. Direct application of butyrate to colonocytes from germ-free mice had a similar effect. Last, Donohue et al. established that butyrate acts as an energy source in this context, rather than as a histone deacetylase inhibitor, its other well-known function.

This study by Donohue et al. is a rare example of mechanistic work in an emerging field in which, so far, most efforts have been taxonomical (characterizing gut microbial populations) and correlative. —JCL

Cancer: Not enough nucleotides

Credit: Equinox Graphics / Photo Researchers, Inc.

Genomic instability is a hallmark of cancer, but it has been unclear how replicative cycles in tumor cells predispose toward instability. New insights into the features of oncogenic cell cycles that might drive instability early in tumor development have been provided by Assaf Bester et al. in a study published in Cell (145, 435–446).

The authors used a skin cell model in which the Rb-E2F pathway, which normally monitors entry into S phase of the cell cycle and proliferation, was aberrantly activated by oncogene expression. Rb-E2F activation led to keratinocyte transformation and replication defects that promoted instability at 'fragile sites' particularly susceptible to replicative stress.

Keratinocytes with Rb-E2F activation had decreased nucleotide levels, and nucleoside supplementation rescued the observed replication defects and consequent DNA damage, as well as reducing transformation. Cells subjected to oncogenic stress upregulated genes involved in replication but did not coordinately upregulate those involved in nucleotide synthesis. The authors suggest a model in which inappropriate activation of the Rb-E2F pathway forces cells to replicate without sufficient nucleotides to support this replication, thus subjecting them to DNA damage and instability. —MS

Neuroscience: Blues clues

The unearthing of genes linked to depression could lead to the discovery of new treatments. Now, Martin A. Kohli et al. report that a polymorphism near SLC6A15, which encodes an amino acid transporter in neurons, increases the risk for depression in a genome-wide association study (Neuron 70, 252–265).

The depression-associated polymorphism decreased SLC6A15 expression in the hippocampus and was associated with smaller hippocampal size in depressed individuals. A strain of mice prone to stress-induced depression expressed lower levels of hippocampal SLC6A15 than a mouse strain that was depression resistant.

Although the researchers did not elucidate why decreased SLC6A15 expression could result in depression, they hypothesized that lower expression of this transporter could allow fewer amino acids into neurons. These amino acids normally serve as precursors for glutamate synthesis, suggesting that lower levels of the transporter would result in reduced glutamate levels. Consistent with this theory, the researchers found lower levels of glutamate in the brains of individuals with the depression-associated polymorphism. —EC

Immunology: Colonizing the gut

Commensal bacteria in the gut present molecular patterns such as Toll-like receptor (TLR) ligands to the immune system and yet—unlike pathogens—escape immune-mediated elimination. Round et al. now report on the mechanisms by which one such commensal, Bacteroides fragilis, induces immune tolerance that permits gut tissue colonization (Science doi:10.1126/science.1206095).

It's known that B. fragilis does not induce T helper type 17 (TH17) cells in the gut, and polysaccharide A (PSA) in the capsule of this bacterium induces interleukin-10 (IL-10) production, induces regulatory T cell development and signals through TLR2. Round et al. now show that suppression of TH17 development and induction of IL-10 by PSA are necessary for B. fragilis to bind gut tissue. In the absence of PSA, B. fragilis induces IL-17A secretion by cells in the gut and fails to associate with the colonic crypts to the extent seen with wild-type bacteria. Blocking IL-17A action with an antibody restored the normal pattern of tissue colonization. Inhibition of TH17 responses also required TLR2-expressing CD4+ T cells, indicating that the induction of IL-10 by the interaction of PSA with TLR2 on CD4+ T cells was needed for B. fragilis to bind the gut tissue. The findings reveal an interplay between the host immune system and microbes that affects the makeup of the tissue-associated gut flora that may—as we learn more about the importance of the gut microbiome—ultimately influence disease. —AF

Written by Eva Chmielnicki, Kevin Da Silva, Alison Farrell, Juan Carlos López and Meera Swami.

Infection: HIV vaccine requires persistence

Thirty years after the first diagnosed case of AIDS in humans, we still have no vaccine to prevent or treat this disease. Louis Picker and his colleagues now report the striking protective efficacy of a cytomegalovirus (CMV)-based vaccine against SIV infection in rhesus macaques (Nature doi:10.1038/nature10003).

The work extends a previous study by these authors (Nat. Med. 15, 293–299, 2009) and shows that 50% of macaques vaccinated with rhesus CMV vectors encoding SIV proteins and subsequently challenged with SIV were protected from progressive infection for more than one year.

Credit: Russell Kightley / Photo Researchers, Inc.

The authors attribute the protection to an increase in SIV-specific effector memory T cell responses at potential sites of CMV replication and to persistence of the CMV vaccine, which contrast to the central memory T cell responses in lymphoid tissues induced by nonpersistent DNA vaccines. The levels of SIV-specific antibodies did not correlate with protection. Interestingly, CMV-vaccinated macaques that controlled viral replication did not show viral rebound after depletion of either CD4+ or CD8+ T cells, suggesting that the virus may have been cleared from these animals or that low levels of residual T cells were sufficient to control viral replication.

The findings suggest that CMV might provide a new platform for HIV vaccine development, but more insight into the mechanisms underlying protection is needed. Some of the practical challenges yet to be addressed include the regulatory hurdles to using a live CMV vector in humans and the effect preexisting CMV infection in humans might have on induction of protective immunity. —AF

New from NPG

A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia

Klinakis, A. et al. Nature 473, 230–233 (2011).

A new twist is added to the role of Notch signaling in tumorigenesis with the finding that inactivation of Notch can lead to the development of chronic myelomonocytic leukemia, suggesting that Notch can have both tumor-promoting and tumor-suppressive roles in blood cancers.

Neuronal activity regulates the regional vulnerability to amyloid-β deposition

Bero, A.W. et al. Nat. Neurosci. doi:10.1038/nn.2801 (1 May).

In a mouse model of Alzheimer's disease, brain regions with increased metabolic activity show greater concentrations of amyloid-b (Ab) in their interstitial fluid, thus promoting local Ab aggregation and plaque formation. The selective pattern of Ab plaque deposition in Alzheimer's brains may thus depend on local neuronal activity.

The encephalitogenicity of T H 17 cells is dependent on IL-1– and IL-23–induced production of the cytokine GM-CSF

El-Behi, M. et al. Nat. Immunol. doi:10.1038/ni.2031 (24 April).

RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation

Codarri, L. et al. Nat. Immunol. doi:10.1038/ni.2027 (24 April).

Two studies identify a key mechanism in the development of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Interleukin-23 (IL-23) induces production of the cytokine granulocyte-macrophage colony–stimulating factor (GM-CSF) by T helper 17 cells, leading to autoimmune inflammation. Therefore, blocking GM-CSF may be a potential strategy for treating multiple sclerosis.

Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

O'Roak, B.J. et al. Nat. Genet. doi:10.1038/ng.835 (15 May).

Exome sequencing of 20 individuals with sporadic autism spectrum disorders (ASDs) and their parents identifies 21 de novo mutations, 11 of which altered the cognate protein, highlighting the importance of de novo mutations in the development of this group of ASDs.