Stem Cell Research

Induced Pluripotent Stem Cells Produced With Mutated Parkinson's Gene

Using adult stem cells, researchers have generated the type of human neuron specifically damaged by Parkinson’s disease (PD) and used various drugs to stop the damage. Working as part of a National Institute of Neurological Disorders and Stroke consortium, the team created three lines of induced pluripotent stem (iPS) cells derived from the skin cells of adults with PD. Two of the cell lines had the mutated LRKK2 gene, a hallmark of the most common genetic cause of PD.

“Our study suggests that some failed drugs should actually work if they were used earlier, and especially if we could diagnose PD before tremors and other symptoms first appear,” said Ted M. Dawson, M.D., Ph.D., a professor of neurology at the Johns Hopkins University School of Medicine.

New Technique Converts Stem Cells Into Brain Cells More Simply, More Quickly, and More Safely Than Previous Research Suggested Possible

By adding two molecules, researchers have discovered a surprisingly simple way of starting the stem cells' journey to become finished brain cells. The process mimics the brain's natural development by releasing signals that are part of the normal development process. Experiments in animal models have shown that the cells quickly adapt in the brain and behave like normal brain cells.

"We have used the new protocol to make dopamine neurons, the type of neuron that is affected by Parkinson's disease," said  Malin Parmar, associate professor of neurobiology at Lund University. "And for the first time, we are seriously talking about these cells as being good enough to move forward for transplantation in patients. The next step is to test the process on a larger scale and to carry out more pre-clinical safety tests."

Researchers Find First Step In Strategy For Parkinson's Disease Induced Pluripotent Stem Cell Replacement Therapy

Induced pluripotent stem cells (iPSC) are a promising avenue for cell replacement therapy in neurologic diseases. For example, mouse and human iPSCs have been used to generate dopaminergic (DA) neurons that improve symptoms in rat Parkinson's disease models.

Now researchers have evaluated the growth, differentiation, and function of human-derived iPSC-derived neural progenitor cells (NPCs) in a primate model, and have elucidated their therapeutic potential.

"We developed a series of methods to induce human iPSCs to become NPCs, using a feeder-free culture method, and grafted NPCs at different stages of differentiation into the brain of a monkey PD* model," said Jun Takahashi, MD, PhD, of Kyoto University. "We developed a method to evaluate the growth and DA activity of the grafts using magnetic resonance imaging (MRI), positron emission tomography (PET), immunocytochemistry, and behavioral analyses, all of which will be useful in preclinical research."

Researchers Find Solution to Cell Death Problem Vexing Stem Cell Research

Human pluripotent stem (hPS) cells can generate any given cell type in the adult human body, which is why they are of interest to stem cell scientists working on finding stem cell therapies for spinal cord injuries, Parkinson's disease, burns, heart disease, diabetes, arthritis, and other ailments.

Before hPS cell technologies can be translated into clinical applications, however, some obstacles must first be overcome.

One such obstacle frustrating stem cell researchers is “cell death” that the major types of hPS cells, including human embryonic stem cells and human induced pluripotent stem cells, mysteriously undergo when cultured as single cells, rendering them less suitable for research.

Researchers at the University of California, Riverside now show that a molecular motor, called “nonmuscle myosin II” (NMII), which exists naturally inside each hPS cell and controls various cellular functions, triggers the death of hPS cells when they are broken down to single cells.

While many details of how exactly NMII works remain unknown, a wide consensus among researchers is that NMII induces a contraction of the main internal components of the cells, eventually resulting in cell death.

Researchers Transform Mouse Skin Cells Into Neurons, Skipping Induced Pluripotent Stem Cell Stage

The future of regenerative medicine continues to depend on the type of stem cell that is proven most effective, most scalable, and most time and cost efficient to produce.  Approaches include embryonic stem cells, adult stem cells, Induced pluripotent stem cells, from both autologous and allogeneic sources.  One of our Sector Companies, International Stem Cell Corp., is attempting to create a stem cell bank based on parthenogenic stem cells derived from unfertilized eggs (oocytes).  Such a bank would have the following advantages:

1. A scalable bank would contain a manageable number of stem cell lines that will be immunological matches for large patient populations of different ethnic origin.


2. Unlike induced pluripotent stem (iPS) cells these would not involve extensive gene manipulation, which to this point in time have largely unknown biological impact.

We point this out in order to ask ourselves what the potential impact on such a stem cell bank might be from new study results obtained by researchers at Stanford University.  Since human iPS cells were first created in late 2007, the emphasis has been on developing these cells in a faster, cheaper way that also provides safe and predictable biological results when used in regenerative therapies.

But what if the iPS phase can be skipped entirely?  Will adult cells converted, for example, directly  into nerve cells be an eventual solution to Parkinson's Disease?  Or will parthenogenic, or some other more basic, more embryonic-like, cell provide the answer.  Perhaps both will be a solution and success in the market, as well as in therapy, will be a function of efficiency from origin to therapeutic use, and resultant lower cost. Perhaps neither will be universally useful in general therapy, but will be more effective for therapies in particular parts of the body.  At this stage no one knows for sure.  What we do know is that knowledge is expanding rapidly as shown in this current Stanford study.

Stanford researchers have succeeded in transforming mouse skin cells in a laboratory dish directly into functional nerve cells with the application of just three genes. The cells make this transition without first becoming a pluripotent type of stem cell.

Breakthrough Produces Parkinson’s Disease Patient-Specific Stem Cells Free Of Reprogramming Genes

Whitehead Institute researchers have developed a novel method to remove potential cancer-causing genes during the reprogramming of skin cells from Parkinson’s disease patients into an embryonic-stem-cell-like state. The resulting induced pluripotent stem (iPS) cells were used to derive dopamine-producing neurons, the cell type that degenerates in Parkinson’s disease patients. This marks the first time researchers have generated human iPS cells that have maintained their embryonic stem-cell-like properties after the removal of reprogramming genes.

All of you familiar with stem cell developments know researchers have been reprogramming adult cells into Induced Pluripotent Cells (iPS) by using viruses to transfer four genes into the cells’ DNA. Although necessary for reprogramming cells, these genes, the known oncogene c-Myc in particular, also have the potential to cause cancer.  In addition, the four genes interact with approximately 3000 other genes in the cell, which may change how the cell functions. Therefore, leaving the genes in successfully reprogrammed cells may cause unintended alterations that limit the cells’ applicability for therapeutic use, for drug screens or to study disease in cell culture.

To solve this problem Whitehead Institute researchers used viruses to transfer the reprogramming genes and a gene coding for the enzyme Cre into skin cells from Parkinson’s disease patients. The reprogramming genes were bracketed by short DNA sequences, called loxP, which are recognized by the enzyme Cre.

UC Irvine Results Confirm MIT Brain Stem Cell Location Study

Evidence indicates that the true stem cells in the mammalian brain are the ependymal cells that line the ventricles in the brain and spinal cord, rather than cells in the subventricular zone as biologists previously believed. Brain ventricles are hollow chambers filled with fluid that supports brain tissue, and a layer of ependymal cells lines these ventricles. This finding at UC Irvine supports the finding of MIT researchers posted here a few days ago.

UC Irvine scientists have shown that with proper stimulation they can produce new brain cells to replace those lost to disease or injury.  Ependymal cells line the fluid-filled ventricles, so a drug to activate the cells could theoretically travel through this fluid directly to the stem cells.

A First: Embryonic Stem Cells Coaxed To Become Nerve Cells

One of the most difficult challenges in stem cell research is figuring out exactly what biological events cause stem cells to differentiate into specific, functioning cells in the body.  For nerve cells this mystery may now be solved. For the first time, researchers have genetically programmed embryonic stem (ES) cells to become nerve cells when transplanted into the brain.

Stroke, Alzheimer’s, Parkinson’s and Huntington’s disease destroy brain cells, causing speech and memory loss and other debilitating consequences. Transplanting neuronal brain cells could restore at least some brain function, just as heart transplants restore blood flow.  But until now there has been no reliable method of coaxing stem cells to become nerve cells.

“We found that we could create new nerve cells from stem cells, transplant them effectively and make a positive difference in the behavior of the mice,” said Stuart A. Lipton, M.D., Ph.D., professor and director of the Del E. Webb Neuroscience, Aging, and Stem Cell Research Center at The Burnham Institute. “These findings could potentially lead to new treatments for stroke and neurodegenerative diseases such as Parkinson’s disease.”

Parkinson's Disease: Reprogrammed Stem Cells Reduce Symptoms

    "This is the first demonstration that reprogrammed cells can integrate into the neural system or positively affect neurodegenerative disease," said Marius Wernig, lead author of the article and a postdoctoral researcher in Rudolf Jaenisch's lab.  Dr. Jaenisch is a member of the Whitehead Institute for Biomedical Research.

    These experiments fashioned rat skin cells into induced pluripotent stem cells (IPS - adult stem cells reprogrammed to become embryo-like stem cells) by reprogramming them, using retroviruses, to move four preselected genes into the cells' DNA.  The IPS cells were then prompted to differentiate into neural precursor cells and dopamine neurons.  In one experiment they were transplanted into the brain cavities of mouse embryos.  Later analysis showed they had integrated into surrounding brain tissue.

Parkinson's Disease: Transplanted Dopamine Cells Develop Changes Characterisitc Of Parkinson's Disease

The autopsy of a patient with Parkinson's who received a dopamine transplant 14 years ago revealed that dopamine cells transplanted into the brain had developed pathologic changes characteristic of  the disease. "Dopamine cells are transplanted into the brain of Parkinson's patients in the hope that they can replace those  that degenerate and thereby improve symptoms of the disease, " said Dr. C Warren Olanow, M.D., Professor and Chairman of Neurology and Director of the Robert and John M. Bendheim Parkinson's Disease Center at Mount Sinai School of Medicine. "This study shows that implanted cells can become affected by the disease process and thereby limits the long term utility of the approach."

    Dr. Olanow went on to say, "These findings do not mean that transplant strategies such as stem cells can not be made to work.  Our findings just represent another obstacle that will have to be overcome."   

    Parkinson's is a degenerative disorder of the central nervous system that impairs motor skills to an increasing degree over time.

     Read the complete Mount Sinai School of Medicine announcement here.