‘Expand’ Stem Cells

How to Generate New Neurons in the Brain

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Summary: After discovering the importance of cell metabolism in neurogenesis, researchers were able to increase the number of neurons in the brains of adult and elderly mice.

Source: University of Geneva

Some areas of the adult brain contain quiescent, or dormant, neural stem cells that can potentially be reactivated to form new neurons. However, the transition from quiescence to proliferation is still poorly understood.

A team led by scientists from the Universities of Geneva (UNIGE) and Lausanne (UNIL) has discovered the importance of cell metabolism in this process and identified how to wake up these neural stem cells and reactivate them.

Biologists succeeded in increasing the number of new neurons in the brain of adult and even elderly mice.

These results, promising for the treatment of neurodegenerative diseases, are to be discovered in the journal Science Advances.

Stem cells have the unique ability to continuously produce copies of themselves and give rise to differentiated cells with more specialized functions. Neural stem cells (NSCs) are responsible for building the brain during embryonic development, generating all the cells of the central nervous system, including neurons.


Neurogenesis capacity decreases with age 

Surprisingly, NSCs persist in certain brain regions even after the brain is fully formed and can make new neurons throughout life. This biological phenomenon, called adult neurogenesis, is important for specific functions such as learning and memory processes. However, in the adult brain, these stem cells become more silent or ‘‘dormant’’ and reduce their capacity for renewal and differentiation.

As a result, neurogenesis decreases significantly with age.

The laboratories of Jean-Claude Martinou, Emeritus Professor in the Department of Molecular and Cellular Biology at the UNIGE Faculty of Science, and Marlen Knobloch, Associate Professor in the Department of Biomedical Sciences at the UNIL Faculty of Biology and Medicine, have uncovered a metabolic mechanism by which adult NSCs can emerge from their dormant state and become active.

‘‘We found that mitochondria, the energy-producing organelles within cells, are involved in regulating the level of activation of adult NSCs,’’ explains Francesco Petrelli, research fellow at UNIL and co-first author of the study with Valentina Scandella.

This shows newly produced neurons in the dentate gyrus
Newly produced neurons (red) in the dentate gyrus with cell nuclei (blue) and a marker for immature neurons (green).

The mitochondrial pyruvate transporter (MPC), a protein complex discovered eleven years ago in Professor Martinou’s group, plays a particular role in this regulation. Its activity influences the metabolic options a cell can use.

By knowing the metabolic pathways that distinguish active cells from dormant cells, scientists can wake up dormant cells by modifying their mitochondrial metabolism.


New perspectives 

Biologists have blocked MPC activity by using chemical inhibitors or by generating mutant mice for the Mpc1gene. Using these pharmacological and genetic approaches, the scientists were able to activate dormant NSCs and thus generate new neurons in the brains of adult and even aged mice.

‘‘With this work, we show that redirection of metabolic pathways can directly influence the activity state of adult NSCs and consequently the number of new neurons generated,’’ summarizes Professor Knobloch, co-lead author of the study.

‘‘These results shed new light on the role of cell metabolism in the regulation of neurogenesis. In the long term, these results could lead to potential treatments for conditions such as depression or neurodegenerative diseases’’, concludes Jean-Claude Martinou, co-lead author of the study.

Abstract

Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells

Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood.

We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Despite its metabolic key function, the role of MPC in NSPCs has not been addressed.

We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation.

Furthermore, genetic Mpc1 ablation in vitro and in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice.

These findings highlight the importance of metabolism for NSPC regulation and identify an important pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.

Scientists Discover Method To ‘Expand’ Stem Cells In The Laboratory That Could Lead To New Cancer Treatments

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Stem cells used in cell-based therapies have so far saved countless lives that may have otherwise been lost to cancer or birth defects. But such therapies are always subject to finding sufficient quantities of stem cells from a donor. But now, scientists from the University of Colorado School of Medicine have discovered a novel process that allows them to expand production of stem cells. An article on the research has been published Friday in PLOS ONE.

Stem cell cultivation

Stem cell cultivation Growing stem cells in the laboratory can greatly help in developing interventions for several autoimmune and metabolic conditions.

The scientists have uncovered the molecular code, or the process that regulates how the stem cells differentiate to produce more stem cells and retain their stem-cell characteristics. The discovery has generated great excitement among researchers, who hope the findings will aid in a cure for cancers, inborn immunodeficiency and metabolic conditions, and autoimmune diseases.

Importance of Stem Cells

Stem cells are the internal repair system of the body. Their ability to divide and produce more stem cells enables them to replenish old and worn out tissues with new ones. They also have the unique property of differentiating into specialized cells with specialized functions, such as muscle cells, red blood cells, or brain cells. But such differentiation in organs, like the pancreas or the heart, requires specialized conditions.

Scientists have been trying for years to reproduce these specialized conditions that would allow stem cells to differentiate in the laboratory to be used for regenerative and cell-based therapies.

“Use of stem cells to treat cancer patients who face bone marrow transplants has been a common practice for four decades,” said Yosef Refaeli, lead scientist of the study, in a statement. “The biggest challenge, however, has been finding adequate supplies of stem cells that help patients fight infection after the procedure.”

To overcome this, the team developed protein products that can be directly administered to blood stem cells to encourage them to multiply without permanent genetic modifications. The technology worked on blood stem cells obtained from cord blood, adult bone marrow, or peripheral blood from adults.

“Most of those approaches have been limited by the nature of the resulting cells or the inadequate number of cells produced,” said Gates Stem Cell Center Director Dennis Roop, referring to previous attempts to “grow” stem cells in a lab, which have not always been successful.

“The ability to multiply blood stem cells from any source in a dish will be critical for adoption of this new technology in clinics,” said Brian Turner, one of the lead authors of the study.

The researchers are now attempting to start human clinical trials, which will involve attempting blood stem cell expansion in patients suffering from inborn immunodeficiency conditions, like SCID and sickle cell anemia, to metabolic conditions, like Hurler’s disease or Gaucher syndrome, autoimmune diseases like multiple sclerosis and lupus, or cancers such as lymphoma, myeloma, and other types of solid tumors.

Source: Rafaeli Y, Turner B, et al. PLOS ONE. 2014.