How stimulating! A new way to repair broken bones

For those of us who live in earthquake country the recent devastating quakes in Nepal are a reminder, as if we needed one, of the danger and damage these temblors can cause. Many of those injured in the quake suffered severe bone injuries – broken legs, crushed limbs etc. Repairing those injuries is going to take time and expert medical care. But now a new discovery is opening up the possibility of repairing injuries like this, even regenerating the broken bones, in a more efficient and effective way.

shutterstock_18578173A study published in Scientific Reports  shows that it is possible to regrow bone tissue using protein signals from stem cells. Even more importantly is that this new bone tissue seems to be just as effective, in terms of the quantity and quality of the bone created, as the current methods.

In a news release senior author Todd McDevitt, Ph.D., said this shows we might not even need whole stem cells to regenerate damaged tissue:

“This proof-of-principle work establishes a novel bone formation therapy that exploits the regenerative potential of stem cells. With this technique we can produce new tissue that is completely stem cell-derived and that performs similarly with the gold standard in the field.”

McDevitt – who is now at the Gladstone Institutes thanks to a research leadership award from CIRM  – extracted the proteins that stem cells produce to help regenerate damaged tissues. They then isolated the particular factors they needed to help regenerate bones, in this case bone morphogenetic protein or BMP. That BMP was then transplanted into mice to stimulate bone growth. And it worked.

While this compares favorably to current methods of regenerating or repairing damaged bones it has a few advantages. Current methods rely on getting bones from cadavers and grinding them up to get the growth factors needed to stimulate bone growth. But bones from cadavers can often be in short supply and the quality is highly variable.

As McDevitt says:

“These limitations motivate the need for more consistent and reproducible source material for tissue regeneration. As a renewable resource that is both scalable and consistent in manufacturing, pluripotent stem cells are an ideal solution.”

He says the next step is to build on this research, and try to find ways to make this method even more efficient. If he succeeds he says it could open up new ways of treating devastating injuries such as those sustained by soldiers in battle, or by earthquake victims.

CIRM Creativity Student Hanan Sinada’s ‘Extraordinary’ Journey as a Budding Scientist

This summer we’re sponsoring high school interns in stem cell labs throughout California as part of our annual Creativity Program. We asked those students to share their experiences through blog posts and videos.

Today, we hear from Hanan Sinada, who has been busy at the Gladstone Institutes in San Francisco.

Extraordinary. That is the word I would use to describe my time here at Gladstone. This summer I have been an intern at the Gladstone Institute of Neurology, studying microglia. The brain has two main types of cells. Those cells are neurons and glial cells. Glia makes ninety percent of the cells in your brain. Although the word “glia” is derived from the Greek word meaning “glue”, glia cells are more like the support system that surround the neurons in the brain. Many people have not heard of glial cells because they are the dark matter of the brain and not involved in synaptic transition. However, glial cells have many significant functions in the central nervous system (CNS). Their main functions are to supply oxygen and nutrients to the neurons, hold neurons in place, destroy infectious agents, eliminate dead cells, and provide insulation (myelin) to neurons.

Hanan Sinada with her mentor, Gladstone Postdoctoral Researcher Dr. Grietje Krabbe

Hanan Sinada with her mentor, Gladstone Postdoctoral Researcher Dr. Grietje Krabbe

There are three main types of glial cells: microglia, astrocytes, and oligodendrocytes. In my research we focus specifically on microglial cells. Microglia only make up 10-15 percent of the total glia population. Microglia serve as the central nervous system’s macrophages. One function of microglia is to act as antigen presenting cells. Two other roles of the microglia are phagocytosis and cytotoxicity. In cytotoxicity, microglia release cytotoxic substances such as Nitric Oxide (NO) or hydrogen peroxide (H2O2), to damage neurons that have been infected. This leads to cell death. Microglia’s main function is to maintain homeostasis. As a result, microglia are constantly scavenging for apoptotic cells, infectious agents, or any foreign material. Microglia are the main orchestrators of the inflammatory response in the central nervous system (CNS). When an injury occurs in the spinal cord or the brain, microglia release cytokines that cause inflammation in that given area.

In my research we look closely at microglia because they are related to many neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. My lab started to question about what would happen if we annihilated all the microglia in the brain. Would it decrease the possibility of avoiding the development of those diseases? So we gave wild type mice a drug that depleted all the microglia in the brain, and surprisingly enough the microglia repopulated the brain rapidly after a couple of days. By doing immunohistochemistry and using certain markers, I was able to find where this new microglia-like cell was coming from. From previous studies we already know that this new microglia is not from the periphery. Monocytes cannot cross the blood brain barrier to replace the microglia. We believe that this new microglia is coming from progenitor cell (a type of stem cell). However, we do not know which cell type is giving rise to this new microglia population.

Before starting my internship I did not know that it was going to be the most amazing and interesting learning experience I have ever had in my life. Although every now and then I would have a science crisis, such as having to change antibody because a certain staining would not work, I am so happy and lucky to be doing this cutting edge research. Not only did I learn so much but I am proud to say that I have contributed to the future of science.

What was Old is New Again: Scientists Transplant Brain Cells into Aged Mice and Reverse Memory Loss

Alzheimer’s disease starts with small, almost imperceptible steps. And then it builds. Sometimes slowly over a period of decades, other times more quickly—in just a matter of years. But no matter the speed of progression, the end outcome is always the same.

Transplanted cells (shown in green) in the hippocampus, 3 months after transplantation.  Cell nuclei are labeled in blue.  [Credit: Leslie Tong and Yadong Huang/Gladstone Institutes]

Transplanted cells (shown in green) in the hippocampus, 3 months after transplantation. Cell nuclei are labeled in blue. [Credit: Leslie Tong and Yadong Huang/Gladstone Institutes]

The sixth leading cause of death in the United State, Alzheimer’s develops as brain cells, or neurons, are destroyed over time. The hippocampus, the brain’s memory center, is the hardest hit, which is why memory loss is the single most common—and most devastating—symptom of the disease.

As a result, scientists have looked to the field of regenerative medicine to replace the vital cells lost to Alzheimer’s. And now, researchers at the Gladstone Institutes in San Francisco have made an important step towards that goal.

Reporting in the latest issue of the Journal of Neuroscience, researchers in the laboratory of Dr. Yadong Huang have successful transplanted early-stage brain cells, called “neuron progenitor cells,” into aged mice that have been modified to mimic Alzheimer’s symptoms. And after doing so, what they saw was extraordinary.

Not only did the cells survive the transplantation—a feat in and of itself—they began to grow and integrate into the molecular circuitry of the brain. And that’s when they noticed changes to the animals’ behavior.

These mice, whose age corresponded to humans in late-stage adulthood, were living with physical signs of memory loss. But after the cell transplants, the team saw signs that memory and learning were restored.

Leslie Tong, a graduate student at Gladstone and the University of California, San Francisco and the paper’s first author, elaborated on the importance of these findings in a news release:

“Working with older animals can be challenging from a technical standpoint, and it was amazing that the cells not only survived but affected activity and behavior.”

For a brain to function normally, there should be a balance between two types of neurons: ‘excitatory’ neurons, that act as the brain’s gas pedal, and ‘inhibitory’ neurons that serve as the brake. If this balance between these two cell types gets thrown out of whack, normal function is disrupted—and cells, especially the inhibitory neurons, degrade and die. Combined with other factors, such as genetic risk and the buildup of toxic proteins—this imbalance plays a key role in the dysfunction that eventually leads to Alzheimer’s.

The success of this treatment not only reveals the importance of maintaining this balance in memory and learning, but is also proof of concept that if neurons are lost—they can in principle be replaced.

Huang is particularly excited about the therapeutic potential of these findings. As he stated in the same news release:

“The fact that we see a functional integration of these cells into the hippocampal circuitry and a…rescue of learning and memory deficits in an aged model of Alzheimer’s disease is very exciting.”

This study, which was supported in part by CIRM, points towards several possible therapeutic strategies that could one day help human brains ravaged by Alzheimer’s regrow the cells they’ve lost—and repair the damage to learning and memory that today remains irreparable. According to Huang:

“This study tells us that if there is any way we can enhance inhibitory neuron function in the hippocampus, like through the development of small molecule compounds, it may be beneficial for Alzheimer’s disease patients.”