Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques

A cell-based therapy for the replacement of dopaminergic neurons has been a long-term goal in Parkinson’s disease research. Here, we show that autologous engraftment of A9 dopaminergic neuron-like cells induced from mesenchymal stem cells (MSCs) leads to long-term survival of the cells and restoration of motor function in hemiparkinsonian macaques. Differentiated MSCs expressed markers of A9 dopaminergic neurons and released dopamine after depolarization in vitro. The differentiated autologous cells were engrafted in the affected portion of the striatum. Animals that received transplants showed modest and gradual improvements in motor behaviors. Positron emission tomography (PET) using [¹¹C]-CFT, a ligand for the dopamine transporter (DAT), revealed a dramatic increase in DAT expression, with a subsequent exponential decline over a period of 7 months. Kinetic analysis of the PET findings revealed that DAT expression remained above baseline levels for over 7 months. Immunohistochemical evaluations at 9 months consistently demonstrated the existence of cells positive for DAT and other A9 dopaminergic neuron markers in the engrafted striatum. These data suggest that transplantation of differentiated autologous MSCs may represent a safe and effective cell therapy for Parkinson’s disease.

Discovery of pathway leading to depression reveals new drug targets

Scientists have identified the key molecular pathway leading to depression, revealing potential new targets for drug discovery, according to research led by King’s College London’s Institute of Psychiatry. The study, published in Neuropsychopharmacology, reveals for the first time that the ‘Hedgehog pathway’ regulates how stress hormones, usually elevated during depression, reduce the number of brain cells.

Depression affects approximately 1 in 5 people in the UK at some point in their lives. The severity of symptoms can range from feelings of sadness and hopelessness to, in the most severe cases, self-harm or suicide. Treatment for depression involves either medication or talking treatment, or usually a combination of the two.

Recent studies have demonstrated that depression is associated with a reduction in a brain process called ‘neurogenesis’- the ability of the brain to produce new brain cells. However, the pathway responsible for this process has, until now, remained unknown.

In this study, Dr Christoph Anacker from the Centre for the Cellular Basis of Behaviour (CCBB) at King’s Institute of Psychiatry and his team studied human stem cells, which are the source of new cells in the human brain, to investigate the effect of stress hormones on brain cell development. The study was funded by the National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King’s College London and the Medical Research Council UK.

Stress hormones, such as cortisol, are generally elevated in stress and depression. The team studied stem cells in a laboratory and found that high concentrations of cortisol damaged these stem cells and reduced the number of newborn brain cells. They discovered that a specific signalling mechanism in the cell, the ‘Hedgehog pathway’, is responsible for this process. Then, using an animal model, the team confirmed that exposure to stress inhibited this pathway in the brain.

Finally, in order to test the findings, the researchers used a compound called purmorphamine, which is known to stimulate the Hedgehog pathway. They found that by using this drug, they were able to reverse the damaging effects of stress hormones, and normalise the production of new brain cells.

Lipid metabolism regulates the activity of adult neural stem cells

Neural stem cells generate thousands of new neurons every day in two regions of the adult brain: the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus. This process, called adult neurogenesis, is critical for a number of processes implicated in certain forms of learning and memory. Impaired adult neurogenesis has been associated with a number of diseases such as depression, epilepsy, and Alzheimer’s disease.

A team led by Sebastian Jessberger, Professor of Neurosciences at the Brain Research Institute, has now identified a novel mechanism that plays a key role in adult neurogenesis and is required for the life-long activity of neural stem cells. Prof. Jessberger believes that “this finding will hopefully give us a new target to develop novel drugs against depression or neurodegenerative diseases”. The results of this study were published on December 2^nd in the scientific journal Nature.

Stem cells produce their own lipids

Researchers in his group could show that stem cells depend on glucose-derived production of new fatty acids and lipids. When the key enzyme of this pathway, fatty acid synthase (Fasn), is blocked in neural stem cells, they loose their ability to divide which results in a reduction in newborn neurons.

To prevent the constant division of neural stem cells, this pathway is regulated by a protein called Spot14, which inhibits lipid synthesis. Controlling Fasn activity is important to make sure that stem cells do not divide too often, which could lead to a premature exhaustion or depletion of the stem cell pool. Surprisingly, the metabolic state of neural stem cells seems to be fundamentally distinct from their daughter cells (newborn neurons) and other dividing cells in the central nervous system. These other cell types are able to take up lipids from the blood stream and use them as important structural components of cell membranes but also for signaling events and as an energy source.

Potential target for new drugs

The study published by the Jessberger group has identified a novel target to pharmacologically enhance the activity of neural stem cells in diseases that are associated with reduced levels of newborn neurons, such as depression.

Marlen Knobloch, postdoc in the Jessberger lab and first author of the study, says: “Currently, we have to understand in much greater detail why neural stem cells are in this distinct metabolic state; to this end, we are currently performing experiments in the lab with the aim to enhance neurogenesis through manipulation of lipid metabolism”. However, one must not place too high expectations for the quick development of novel drugs, although for Simon Braun, co-first author of the study, “the hope certainly is to increase the number of newborn neurons by targeting lipid metabolism in the human brain”.

Human Induced Pluripotent Stem Cell-Derived Models to Investigate Human Cytomegalovirus Infection in Neural Cells

Human cytomegalovirus (HCMV) infection is one of the leading prenatal causes of congenital mental retardation and deformities world-wide. Access to cultured human neuronal lineages, necessary to understand the species specific pathogenic effects of HCMV, has been limited by difficulties in sustaining primary human neuronal cultures. Human induced pluripotent stem (iPS) cells now provide an opportunity for such research. We derived iPS cells from human adult fibroblasts and induced neural lineages to investigate their susceptibility to infection with HCMV strain Ad169. Analysis of iPS cells, iPS-derived neural stem cells (NSCs), neural progenitor cells (NPCs) and neurons suggests that (i) iPS cells are not permissive to HCMV infection, i.e., they do not permit a full viral replication cycle; (ii) Neural stem cells have impaired differentiation when infected by HCMV; (iii) NPCs are fully permissive for HCMV infection; altered expression of genes related to neural metabolism or neuronal differentiation is also observed; (iv) most iPS-derived neurons are not permissive to HCMV infection; and (v) infected neurons have impaired calcium influx in response to glutamate.

'Different kind of stem cell' possesses attributes favoring regenerative medicine

A research team at Georgetown Lombardi Comprehensive Cancer Center say the new and powerful cells they first created in the laboratory a year ago constitute a new stem-like state of adult epithelial cells. They say these cells have attributes that may make regenerative medicine truly possible.

In the November 19 online early edition of the Proceedings of the National Academy of Sciences (PNAS), they report that these new stem-like cells do not express the same genes as embryonic stem cells and induced pluripotent stem cells (iPSCs) do. That explains why they don’t produce tumors when they grow in the laboratory, as the other stem cells do, and why they are stable, producing the kind of cells researchers want them to.

"These seem to be exactly the kind of cells that we need to make regenerative medicine a reality," says the study’s senior investigator, chairman of the department of pathology at Georgetown Lombardi, a part of Georgetown University Medical Center.

This study is a continuation of work that led to a breakthrough in December 2011 when Schlegel and his colleagues demonstrated that he and his team had designed a laboratory technique that keep both normal as well as cancer cells alive indefinitely — which previously had not been possible.

They had discovered that adding two different substances to these cells (a Rho kinase inhibitor and fibroblast feeder cells) pushes them to morph into stem-like cells that stay alive indefinitely. When the two substances are withdrawn from the cells, they revert back to the type of cell that they once were. They dubbed these cells conditionally reprogrammed cells (CRCs).

Stanford/Yale study gives insight into subtle genomic differences among our own cells

Stanford University School of Medicine scientists have demonstrated, in a study conducted jointly with researchers at Yale University, that induced-pluripotent stem cells — the embryonic-stem-cell lookalikes whose discovery a few years ago won this year’s Nobel Prize in medicine — are not as genetically unstable as was thought.

The new study, published online Nov. 18 in Nature, showed that what seemed to be changes in iPS cells’ genetic makeup — presumed to be inflicted either in the course of their generation from adult cells or during their propagation and maintenance in laboratory culture dishes — instead are often accurate reflections of existing but previously undetected genetic variations among the cells comprising our bodies.

That’s good news for researchers hoping to use the cells to study disease or, someday, for regenerative medicine. But it raises the question of whether and to what extent we humans are really walking mosaics whose constituent cells differ genetically from one to the next in possibly significant respects, said Alexander Urban, PhD, assistant professor of psychiatry and behavioral sciences. Urban shared senior authorship of the study with bioinformatics professor Mark Gerstein, PhD, and neurobiology professor Flora Vaccarino, MD, both of Yale.

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Biocompatible sponge can be injected to deliver stem cells and drugs into the body

Biocompatible scaffolds, like those developed to stimulate the repair of heart tissue and bone and cartilage in the body, would normally need to be implanted surgically. Now bioengineers at Harvard University have developed a compressible bioscaffold that can be delivered via a syringe before popping back to its original shape inside the body. The material is also able to be loaded up with drugs or living cells that are gradually released as the material breaks down.

The injectable sponge is made up primarily of a seaweed-based jelly called alginate. It is actually a sponge-like gel that is formed through a freezing process called cryogelation. When the water in the alginate solution starts to freeze, pure ice crystals are formed and the surrounding gel becomes more concentrated as it sets. Later, the ice crystal melt to leave a network of large pores that allow liquids and large molecules to easily flow through it. Live cells can be attached to the walls of this network and large and small proteins and drugs can also be held within the alginate jelly itself.

Unlike other alginate gels that are brittle, using this method the researchers were able to produce a strong, compressible gel by carefully calibrating the alginate mixture and the timing of the freezing process.

The research team led by principal investigator David J. Mooney, the Robert P. Pinkas Family Professor of Bioengineering at the Harvard School of Engineering and Applied Sciences (SEAS), demonstrated that cells and drugs can be delivered into the body intact along with the sponge through a small bore needle. Once inside the body, the sponge returns to its original shape and gradually releases its cargo as it breaks down.

“What we’ve created is a three-dimensional structure that you could use to influence the cells in the tissue surrounding it and perhaps promote tissue formation,” explains Mooney. “The simplest application is when you want bulking. If you want to introduce some material into the body to replace tissue that’s been lost or that is deficient, this would be ideal. In other situations, you could use it to transplant stem cells if you’re trying to promote tissue regeneration, or you might want to transplant immune cells, if you’re looking at immunotherapy.”

Worm Regeneration May Lend A Hand in Human Healing

About the size of toenail clippings, planarians are freshwater flatworms that can re-form from tiny slivers. This feature not only lets them repair themselves, but it lets them reproduce by breaking apart and then creating new worms.   

Here are two other important features: More than half of planarian genes have parallels in people, and some of their basic physiological systems operate like ours. By studying how these features behave as the worms regenerate, scientists might move one step closer to learning how to generate or regenerate human tissue and cells, such as insulin-producing cells for people with diabetes or nerve cells for patients with spinal cord injuries.

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