Edited stem cells reverse mouse diabetes

Scientists at Washington University in St. Louis have managed to reverse diabetes in mouse models through the transplantation of CRISPR-edited cells derived from patients with Wolfram syndrome, a monogenic form of type 1 diabetes. Cell therapy to replace the insulin-producing pancreatic cells that are lost in diabetes has been a long-standing goal of regenerative medicine that has been attempted via multiple routes. In their work, the authors used induced pluripotent stem cells (iPSCs) derived from two patients with Wolfram syndrome and differentiated them into pancreatic islet cells via a multistep protocol that included gene editing with CRISPR. The cells were able to reverse established diabetes in mice. “In the future, we suspect that our advanced strategy combining patient iPSCs, gene editing, and differentiation to high-functioning [b] cells and other cell types will produce a viable, personalized cell source for cell therapy in patients with diabetes and other degenerative disorders,” the authors wrote. They published their findings in the April 22, 2020, issue of Science Translational Medicine.

Noncoding TET2 variants affect neurodegeneration risk

Researchers at the Alzheimer’s Disease Neuroimaging Initiative have implicated both loss-of-function and noncoding variants in the enzyme TET2 as risk factors for multiple neurodegenerative disorders. The authors began by comparing individuals with early onset AD and frontotemporal dementia, both of which have string genetic components, to cognitively normal controls. They validated their findings in a larger cohort that included patients with multiple neurodegenerative disorders. TET2 is an enzyme that performs epigenetic modifications. The authors noted that beyond the specific implication of TET2 in neurodegeneration, “the effect sizes in both coding and non-coding variant enrichments were comparable. This point suggests that further investigation of non-coding variation in disease genome sequencing studies holds potential for the identification of new contributors to disease.” They reported their results in the April 23, 2020, issue of the American Journal of Human Genetics.

Pancreatic cancer uses autophagy to hide from immune system

Researchers at New York University School of Medicine have demonstrated that pancreatic cancer cells specifically targeted their major histocompatibility complex class I (MHC-1) for destruction via autophagy as an immune evasion mechanism. MHC-1 molecules present antigens to the immune system, and some mutations in MHC-1 molecules are associated with resistance to checkpoint blockade inhibition. Pancreatic cancer is also resistant to checkpoint blockade, but the resistance-conferring MHC-1 mutations are rarely found in pancreatic tumors. The authors demonstrated that pancreatic tumor cells down-regulated their MHC-1 surface molecules by targeting for destruction by autophagy via the receptor NPR1. The team also found that “inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumor T cell responses and reduced tumor growth in syngeneic host mice,” as well as sensitizing mice to checkpoint blockade. The team published its findings in the April 23, 2020, issue of Nature.

Heart failure hormone has role in sepsis

Scientists at Temple University School of Medicine have identified a role for the hormone B-type natriuretic peptide (BNP) in sepsis. BNP is produced by the heart and lowers blood pressure, and is a prognostic biomarker in heart failure. It has also been proposed as a biomarker in sepsis, where blood pressure can become dangerously low in serious cases. However, whether BNP participated in lowering blood pressure in sepsis had not been clear. The authors showed that the c-Jun N-terminal kinase (JNK) signaling, which also leads to harmful changes in mitochondrial metabolism during sepsis, activated BNP production and led to hypotension. The authors concluded that the present study provides mechanistic insight into the factors underlying septic shock and proposes the design of two treatment strategies to manage critically ill patients with hypodynamic sepsis. They reported their results in the April 23, 2020, issue of JCI Insight.

NRF2 wakes sleeping tumor cells

Investigators at Duke University have delineated metabolic changes that could cause breast tumor cells to exit dormancy and resume proliferating. Dormancy is a troubling feature of certain tumor types, including breast tumors, that enables them to remain in a nondividing state for very long periods. Clinically, that translates into a relapse risk for breast cancer that declines over time, but remains elevated for decades after treatment. How tumor cells enter and exit dormancy remains poorly understood, but there are clearly major metabolic differences between dormancy and proliferation. The authors discovered that “Her2 downregulation in breast cancer cells promotes changes in cellular metabolism, culminating in oxidative stress and compensatory upregulation of the antioxidant transcription factor NRF2. NRF2 is activated during dormancy and in recurrent tumors in animal models and patients with breast cancer with poor prognosis.” Activation of NRF2 accelerated the recurrence of dormant tumors in animal models, while suppression of NRF2 could prevent recurrence. The team reported its results in the April 20, 2020, online issue of Nature Metabolism.

Oral drug can wake up telomerase

Telomerase, the enzyme that can stop the molecular scorekeeping mechanism by which cells keep track of how many divisions they have been through, is critical to keep stem cells able to divide. If telomerase does not function properly in stem cells, diseases, including developmental disorders such as dyskeratosis congenita (DC) and disorders of aging like pulmonary fibrosis (PF), can be the result. Researchers from Boston Children’s Hospital have identified a small molecule, the dihydroquinolizinone RG-7834, that was able to restore telomerase activity in cells in animal models of DC and PF. RG-7834 worked by inhibiting the DNA polymerase PAPD5. The authors concluded that their findings “pave the way for developing systemic telomere therapeutics to counteract stem cell exhaustion in DC, PF and possibly other aging-related diseases.” They reported their results in the April 23, 2020, online issue of Cell Stem Cell.

Cheating cell death improves infarct outcomes

Researchers at Henan University and Temple University have demonstrated that blocking the interaction of (TNF)-related apoptosis-inducing ligand (TRAIL) with its receptor, the death receptor 5 (DR5), prevented cell death and reduced tissue damage after an induced heart attack via both direct and indirect mechanisms. The authors tested the effects of TRAIL blockade in rats, pigs and monkeys. They found that blocking the interaction between TRAIL and its receptor reduced cell death, but it also prevented the migration of immune cells and subsequent inflammation at the site of injury. “Our findings indicate that TRAIL mediates MI directly by targeting cardiomyocytes and indirectly by affecting myeloid cells, supporting TRAIL blockade as a potential therapeutic strategy” for treating heart attacks, the authors wrote. Their work appeared in the April 22, 2020, issue of Science Translational Medicine.

Older siblings’ example turns stem cells into heart cells

Researchers at the University of British Columbia have demonstrated that heart muscle cells that were themselves derived from induced pluripotent stem (iPS) cells could stimulate more iPS cells to differentiate into heart cells. Turning iPS cells into a desired cell type is an ongoing challenge, but one possibility that has worked for some cell types is to culture iPS cells with mature cells of the desired type. The authors demonstrated that co-culturing induced cardiomyocytes (iCMs) and iPS cells was successful but iCM-iPS cell-cell contact was essential for inductive differentiation, and that required overlaying already adherent iPS cells with iCMs. Importantly, that process was achieved “without the exogenous addition of pathway inhibitors and morphogens, suggesting that ‘older’ iCMs serve as an adequate stimulatory source capable of recapitulating the necessary culture environment for cardiac differentiation.” They reported their results in the April 3, 2020, online issue of PLoS ONE.

Lung changes from PD drug hopeful are reversible

An activating mutation in the leucine-rich repeat kinase 2 (LRRK2) is one of the most common genetic causes of Parkinson’s disease (PD), and is a target of experimental PD drugs. However, preclinical testing of such agents, including in primates, has shown that they can lead to changes in kidney and lung tissue. Researchers at the Michael J. Fox Foundation have taken a more detailed look at both the pharmacokinetics and the functional consequences of those changes, and found that they were due to on-target effects of inhibitors. However, changes to lung histology were mild and reversible after treatment withdrawal. Moreover, at doses that could lead to complete inhibition of LRRK2 in the brain, histopathological lung changes were either absent or minimal, “reversible, and did not manifest as functional deficits. Our results suggest that the observed lung effects in nonhuman primates in response to LRRK2 inhibitors should not preclude clinical testing of these compounds for PD,” the authors concluded. Their work appeared in the April 22, 2020, issue of Science Translational Medicine.

Platelets play role in Tylenol toxicity

Scientists at the University of Birmingham have implicated the C-type lectin-like receptor 2 (CLEC-2) in acute liver failure due to acetaminophen overdose. Acetaminophen is the active ingredient in Tylenol and one of the most widely used nonprescription painkillers. It is also toxic to the liver at high doses, or at lower doses combined with alcohol, and is the most frequent causes of acute liver failure in the U.S. and Europe, and there are no treatments that can reverse established liver failure. Previous work had implicated platelet accumulation in the acetaminophen toxicity, but the molecular mechanism leading to liver toxicity had not been worked out. In their experiments, the researchers showed that acute liver injury led to increased levels of podoplanin, which binds the platelet receptor CLEC-2. The resulting platelet aggregation affected cytokine production and ultimately reduced the ability of neutrophils to repair the liver. The authors noted that “since CLEC-2 mediated platelet activation is independent of major hemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure.” Their findings appeared in the April 22, 2020, issue of Nature Communications.

No Comments