Skin Cells from Alzheimer’s Disease Were Turned into Cultured Neurons Using iPSC Technology

Scientists from the University of California, San Diego School of Medicine, have created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer’s, using induced pluripotent stem cells from patients with the neurodegenerative disorder. This experiment provides the ability to study the precise abnormalities present in neurons that cause the pathology of this neurodegenerative disease.

Senior study author Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute investigator and director of the UC San Diego Stem Cell Program, noted that the production of highly purified, functional human Alzheimer’s neurons in culture has never been done before. Goldstein said: “It’s a first step. These aren’t perfect models. They’re proof of concept. But now we know how to make them.”

This experiment represents a new method for studying the causes of Alzheimer’s disease. These living cells provide a tool for developing and testing drugs to treat the disorder. According to Goldstein, “We’re dealing with the human brain. You can’t just do a biopsy on living patients. Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory.”

Goldstein and colleagues extracted skin cells called fibroblasts from skin tissues from two patients with familial Alzheimer’s disease. They also used fibroblasts from two patients with sporadic Alzheimer’s disease, and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated them into working neurons. These iPSC-derived neurons from the Alzheimer’s patients exhibited normal electrophysiological activity, formed functional synaptic contacts and displayed tell-tale indicators of Alzheimer’s disease. Also, they possessed higher-than-normal levels of proteins associated with Alzheimer’s disease.

With cultured neurons from Alzheimer’s patients, scientists can more deeply investigate how Alzheimer’s disease begins and chart the biochemical processes that eventually destroy brain cells and produce degeneration of elemental cognitive functions like memory. Currently, Alzheimer’s research depends heavily upon autopsies performed after the patient has died and the damage has been done. Goldstein added, “The differences between a healthy neuron and an Alzheimer’s neuron are subtle. It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results.”

Neurons derived from one of the two patients with sporadic Alzheimer’s disease showed biochemical changes possibly linked to the disease. Thus there may be sub-categories of the disorder and, in the future, potential therapies might be targeted to specific groups of Alzheimer’s patients.

Cultured Smooth Muscle Cells are Formed from Stem Cells

Laboratory research needs tissue as a model system. Smooth muscle is found in the urogenital system, circulatory system, digestive system, and respiratory systems of the human body. Various diseases affect smooth muscle and being able to work on cultured smooth muscle would greatly advance the ability of medical researchers to find treatments for smooth muscle disorders.

To address this need, Cambridge University scientists have devised a protocol for generating different types of vascular smooth muscle cells (SMCs) using cells from patients’ skin. This work could lead to new treatments and better screening for cardiovascular disease.

The Cambridge group used embryonic stem cells and reprogrammed skin cells. Skin cells were turned into induced pluripotent skin cells (iPSCs), which were then differentiated into SMCs. They found that they could create all the major vascular smooth muscle cells in high purity using iPSCs. This technique can also be scaled up to produce clinical-grade SMCs.

The scientists created three subtypes of SMCs from these different types of stem cells. They also showed that various SMC subtypes responded differently when exposed to substances that cause vascular diseases. They concluded that differences in the developmental origin play a role in the susceptibility of SMCs to various diseases. Furthermore, the developmental origin of specific SMCs might part some role in determining where and when common vascular diseases such as aortic aneurysms or atherosclerosis originate.

Alan Colman MD, Principle Investigator of the Institute of Medical Biology at Cambridge University, said: “This is a major advance in vascular disease modeling using patient-derived stem cells. The development of methods to make multiple, distinct smooth muscle subtypes provides tools for scientists to model and understand a greater range of vascular diseases in a culture dish than was previously available.”

French Lab Finds Genetic Abnormalities in Embryonic Stem Cell-Derived Neuronal Derivatives

Human pluripotent stem cells represent a tremendous potential for human treatment, but the mutations introduced into these cells during their derivation renders the safety of these cells questionable. Some French researchers have even generated some cautionary data that suggests that additional quality controls are needed to ensure that neural derivatives of human pluripotent stem cells are not genetically unstable. Such cells are currently being tested in clinical trials, and there is a need to ensure that they are genetically sound.

Human stem cells capable of giving rise to any fetal or adult cell type are known as pluripotent stem cells. It is hoped that such cells, the most well-known being human embryonic stem cells (hESCs), can be used to generate cell populations that can be used in therapeutic regiments. Presently, neural derivatives of embryonic stem cells are being tested in clinical trials.

Nathalie Lefort and colleagues at the Institute for Stem cell Therapy and Exploration of Monogenic Diseases (France) have shown that neural derivatives of human embryonic stem cells frequently acquire extra material from the long arm of chromosome 1 (1q). This particular chromosomal defect is sometimes seen in some blood cell cancers and pediatric brain tumors that have a rather poor clinical prognosis. Fortunately, when Lefort and her colleagues implanted these abnormal neural cells into mice, they were unable to form tumors in mice.

Neil Harrison of the University of Sheffield (U.K.) has commented on Lefort’s work in an accompanying article that these data raise safety issues relevant for the therapeutic use of embryonic stem cell derivatives. The fact that the same chromosome was affected in all cases suggests that it should be possible to design a screen that can effectively detect and remove genetically abnormal cells.