Human stem cells converted to functional lung cells.


For the first time, scientists have succeeded in transforming human stem cells into functional lung and airway cells. The advance, reported by Columbia University Medical Center (CUMC) researchers, has significant potential for modeling lung disease, screening drugs, studying human lung development, and, ultimately, generating lung tissue for transplantation. The study was published today in the journal Nature Biotechnology.

“Researchers have had relative success in turning human stem cells into heart cells, pancreatic beta cells, intestinal cells, liver cells, and nerve cells, raising all sorts of possibilities for regenerative medicine,” said study leader Hans-Willem Snoeck, MD, PhD, professor of medicine (in microbiology & immunology) and affiliated with the Columbia Center for Translational Immunology and the Columbia Stem Cell Initiative. “Now, we are finally able to make lung and airway cells. This is important because lung transplants have a particularly poor prognosis. Although any clinical application is still many years away, we can begin thinking about making autologous lung transplants — that is, transplants that use a patient’s own skin cells to generate functional lung tissue.”

The research builds on Dr. Snoeck’s 2011 discovery of a set of chemical factors that can turn human embryonic stem (ES) cells or human induced pluripotent stem (iPS) cells into anterior foregut endoderm — precursors of lung and airway cells. (Human iPS cells closely resemble human ES cells but are generated from skin cells, by coaxing them into taking a developmental step backwards. Human iPS cells can then be stimulated to differentiate into specialized cells — offering researchers an alternative to human ES cells.)

In the current study, Dr. Snoeck and his colleagues found new factors that can complete the transformation of human ES or iPS cells into functional lung epithelial cells (cells that cover the lung surface). The resultant cells were found to express markers of at least six types of lung and airway epithelial cells, particularly markers of type 2 alveolar epithelial cells. Type 2 cells are important because they produce surfactant, a substance critical to maintain the lung alveoli, where gas exchange takes place; they also participate in repair of the lung after injury and damage.

The findings have implications for the study of a number of lung diseases, including idiopathic pulmonary fibrosis (IPF), in which type 2 alveolar epithelial cells are thought to play a central role. “No one knows what causes the disease, and there’s no way to treat it,” says Dr. Snoeck. “Using this technology, researchers will finally be able to create laboratory models of IPF, study the disease at the molecular level, and screen drugs for possible treatments or cures.”

“In the longer term, we hope to use this technology to make an autologous lung graft,” Dr. Snoeck said. “This would entail taking a lung from a donor; removing all the lung cells, leaving only the lung scaffold; and seeding the scaffold with new lung cells derived from the patient. In this way, rejection problems could be avoided.” Dr. Snoeck is investigating this approach in collaboration with researchers in the Columbia University Department of Biomedical Engineering.

“I am excited about this collaboration with Hans Snoeck, integrating stem cell science with bioengineering in the search for new treatments for lung disease,” said Gordana Vunjak-Novakovic, PhD, co-author of the paper and Mikati Foundation Professor of Biomedical Engineering at Columbia’s Engineering School and professor of medical sciences at Columbia University College of Physicians and Surgeons.

 

Stem Cells Converted Into Lung Tissue.


Lung transplant recipients have a relatively low 10 year survival rate of about 28%. Cellular rejection of the donor organ occurs about 90% of the time, which brings additional obstacles for the patient and doctors. This might be about to change, as functional lung tissue has been created from human stem cells. The research comes from Hans-Willem Snoeck from the Columbia Center for Translational Immunology and was published in the current edition of Nature Biotechnology.

A couple of years ago, Dr. Snoeck was able to convert stem cells into the precursor endoderm cells that can eventually differentiate into lung cells. This was done with human embryonic stem cells as well as human induced pluripotent stem cells, which involve a bit more work but are easier to come by. Those precursor cells were shown to actually differentiate into six different respiratory tissues, including the coveted type II alveolar cells. which facilitate gas exchange and produce surfactant.

Type 2 alveolar cells, also called pneumocytes, are responsible for producing surfactant, the compound that allows the lungs to remain inflated with air. These type II cells also aid in gas exchange and lung repair.

The lung tissue produced by stem cells could give researchers a unique perspective to study the tissue and learn more about how lung diseases originate. This could lead to better treatment options for lung diseases.

If treatments do not work and transplant becomes inevitable, physicians can use the patient’s own cells to provide a new disease-free organ. This eliminates both the potential for cellular rejection as well as the stress of waiting on the transplant list. To make a replacement lung, researchers would first remove the patient’s lung and decellularize it, leaving only a cartilaginous scaffold. The stem cells would then be used to coat the scaffold and regrow functional tissue to be put back into the patient.

Though it is a long way from getting implanted into a human body, these results are exciting. A patent has been filed by Columbia University for their technique of converting induced pluripotent stem cells into the functional tissue.

Scientists generate “mini-kidney” structures from human stem cells.


Diseases affecting the kidneys represent a major and unsolved health issue worldwide. The kidneys rarely recover function once they are damaged by disease, highlighting the urgent need for better knowledge of kidney development and physiology.

Now, a team of researchers led by scientists at the Salk Institute for Biological Studies has developed a novel platform to study  diseases, opening new avenues for the future application of regenerative medicine strategies to help restore kidney function.

Salk scientists generate “mini-kidney” structures from human stem cells

For the first time, the Salk researchers have generated three-dimensional kidney structures from human stem cells, opening new avenues for studying the development and diseases of the kidneys and to the discovery of new drugs that target human . The findings were reported November 17 in Nature Cell Biology.

Scientists had created precursors of kidney cells using stem cells as recently as this past summer, but the Salk team was the first to coax human stem cells into forming three-dimensional cellular structures similar to those found in our kidneys.

“Attempts to differentiate human stem cells into renal cells have had limited success,” says senior study author Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory and holder of the Roger Guillemin Chair. “We have developed a simple and efficient method that allows for the differentiation of human stem cells into well-organized 3D structures of the ureteric bud (UB), which later develops into the collecting duct system.”

The Salk findings demonstrate for the first time that pluripotent stem cells (PSCs)—cells capable of differentiating into the many cells and tissue types that make up the body—can made to develop into cells similar to those found in the ureteric bud, an early developmental structure of the kidneys, and then be further differentiated into three-dimensional structures in organ cultures. UB cells form the early stages of the human urinary and reproductive organs during development and later develop into a conduit for urine drainage from the kidneys. The scientists accomplished this with both human  and induced  (iPSCs),  from the skin that have been reprogrammed into their pluripotent state.

After generating iPSCs that demonstrated pluripotent properties and were able to differentiate into mesoderm, a germ cell layer from which the kidneys develop, the researchers made use of growth factors known to be essential during the natural development of our kidneys for the culturing of both iPSCs and embryonic stem cells. The combination of signals from these growth factors, molecules that guide the differentiation of stem cells into specific tissues, was sufficient to commit the cells toward progenitors that exhibit clear characteristics of renal cells in only four days.

The researchers then guided these cells to further differentiated into organ structures similar to those found in the ureteric bud by culturing them with kidney cells from mice. This demonstrated that the mouse cells were able to provide the appropriate developmental cues to allow human  to form three-dimensional structures of the kidney.

In addition, Izpisua Belmonte’s team tested their protocol on iPSCs from a patient clinically diagnosed with polycystic  (PKD), a genetic disorder characterized by multiple, fluid-filled cysts that can lead to decreased  and kidney failure. They found that their methodology could produce kidney structures from patient-derived iPSCs.

Because of the many clinical manifestations of the disease, neither gene- nor antibody-based therapies are realistic approaches for treating PKD. The Salk team’s technique might help circumvent this obstacle and provide a reliable platform for pharmaceutical companies and other investigators studying drug-based therapeutics for PKD and other kidney diseases.

“Our differentiation strategies represent the cornerstone of disease modeling and drug discovery studies,” says lead study author Ignacio Sancho-Martinez, a research associate in Izpisua Belmonte’s laboratory. “Our observations will help guide future studies on the precise cellular implications that PKD might play in the context of .”

Scientists succeed in growing human brain tissue in ‘test tubes’.


Complex human brain tissue has been successfully developed in a three-dimensional culture system established in an Austrian laboratory. The method described in the current issue of Nature allows pluripotent stem cells to develop into cerebral organoids – or “mini brains” – that consist of several discrete brain regions. Instead of using so-called patterning growth factors to achieve this, scientists at the renowned Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (OeAW) fine-tuned growth conditions and provided a conducive environment. As a result, intrinsic cues from the stem cells guided the development towards different interdependent brain tissues. Using the “mini brains”, the scientists were also able to model the development of a human neuronal disorder and identify its origin – opening up routes to long hoped-for model systems of the human brain.

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The development of the human brain remains one of the greatest mysteries in biology. Derived from a simple tissue, it develops into the most complex natural structure known to man. Studies of the human brain’s development and associated human disorders are extremely difficult, as no scientist has thus far successfully established a three-dimensional culture model of the developing brain as a whole. Now, a research group lead by Dr. Jürgen Knoblich at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) has changed just that.

 

Brain size matters

Starting with established human embryonic stem cell lines and induced pluripotent stem (iPS) cells, the group identified growth conditions that aided the differentiation of the stem cells into several brain tissues. While using media for neuronal induction and differentiation, the group was able to avoid the use of patterning growth factor conditions, which are usually applied in order to generate specific cell identities from stem cells. Dr. Knoblich explains the new method: “We modified an established approach to generate so-called neuroectoderm, a cell layer from which the nervous system derives. Fragments of this tissue were then maintained in a 3D-culture and embedded in droplets of a specific gel that provided a scaffold for complex tissue growth. In order to enhance nutrient absorption, we later transferred the gel droplets to a spinning bioreactor. Within three to four weeks defined brain regions were formed.”

Already after 15 – 20 days, so-called “cerebral organoids” formed which consisted of continuous tissue (neuroepithelia) surrounding a fluid-filled cavity that was reminiscent of a cerebral ventricle. After 20 – 30 days, defined brain regions, including a cerebral cortex, retina, meninges as well as choroid plexus, developed. After two months, the mini brains reached a maximum size, but they could survive indefinitely (currently up to 10 months) in the spinning bioreactor. Further growth, however, was not achieved, most likely due to the lack of a circulation system and hence a lack of nutrients and oxygen at the core of the mini brains.

 

Microcephaly in mini brains

The new method also offers great potential for establishing model systems for human brain disorders. Such models are urgently needed, as the commonly used animal models are of considerably lower complexity, and often do not adequately recapitulate the human disease. Knoblich’s group has now demonstrated that the mini brains offer great potential as a human model system by analysing the onset of microcephaly, a human genetic disorder in which brain size is significantly reduced. By generating iPS cells from skin tissue of a microcephaly patient, the scientists were able to grow mini brains affected by this disorder. As expected, the patient derived organoids grew to a lesser size. Further analysis led to a surprising finding: while the neuroepithilial tissue was smaller than in mini brains unaffected by the disorder, increased neuronal outgrowth could be observed. This lead to the hypothesis that, during brain development of patients with microcephaly, the neural differentiation happens prematurely at the expense of stem and progenitor cells which would otherwise contribute to a more pronounced growth in brain size. Further experiments also revealed that a change in the direction in which the stem cells divide might be causal for the disorder.

“In addition to the potential for new insights into the development of human brain disorders, mini brains will also be of great interest to the pharmaceutical and chemical industry,” explains Dr. Madeline A. Lancaster, team member and first author of the publication. “They allow for the testing of therapies against brain defects and other neuronal disorders. Furthermore, they will enable the analysis of the effects that specific chemicals have on brain development.”

 

Source: http://medicalxpress.com/Nature.

Turning human stem cells into brain cells sheds light on neural development.


Medical researchers have manipulated human stem cells into producing types of brain cells known to play important roles in neurodevelopmental disorders such as epilepsy, schizophrenia and autism. The new model cell system allows neuroscientists to investigate normal brain development, as well as to identify specific disruptions in biological signals that may contribute to neuropsychiatric diseases.

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Scientists from The Children’s Hospital of Philadelphia and the Sloan-Kettering Institute for Cancer Research led a study team that described their research in the journal Cell Stem Cell, published online today.

The research harnesses human embryonic stem cells (hESCs), which differentiate into a broad range of different cell types. In the current study, the scientists directed the stem cells into becoming cortical interneurons—a class of brain cells that, by releasing theneurotransmitter GABA, controls electrical firing in brain circuits.

“Interneurons act like an orchestra conductor, directing other excitatory brain cells to fire in synchrony,” said study co-leader Stewart A. Anderson, M.D., a research psychiatrist at The Children’s Hospital of Philadelphia. “However, when interneurons malfunction, the synchrony is disrupted, and seizures or mental disorders can result.”

Anderson and study co-leader Lorenz Studer, M.D., of the Center for Stem Cell Biologyat Sloan-Kettering, derived interneurons in a laboratory model that simulates how neurons normally develop in the human forebrain.

“Unlike, say, liver diseases, in which researchers can biopsy a section of a patient’s liver, neuroscientists cannot biopsy a living patient’s brain tissue,” said Anderson. Hence it is important to produce a cell culture model of brain tissue for studying neurological diseases. Significantly, the human-derived cells in the current study also “wire up” in circuits with other types of brain cells taken from mice, when cultured together. Those interactions, Anderson added, allowed the study team to observe cell-to-cell signaling that occurs during forebrain development.

In ongoing studies, Anderson explained, he and colleagues are using their cell model to better define molecular events that occur during brain development. By selectively manipulating genes in the interneurons, the researchers seek to better understand how gene abnormalities may disrupt brain circuitry and give rise to particular diseases. Ultimately, those studies could help inform drug development by identifying molecules that could offer therapeutic targets for more effective treatments of neuropsychiatric diseases.

In addition, Anderson’s laboratory is studying interneurons derived from stem cells made from skin samples of patients with chromosome 22q.11.2 deletion syndrome, a genetic disease which has long been studied at The Children’s Hospital of Philadelphia. In this multisystem disorder, about one third of patients have autistic spectrum disorders, and a partially overlapping third of patients develop schizophrenia. Investigating the roles of genes and signaling pathways in their model cells may reveal specific genes that are crucial in those patients with this syndrome who have neurodevelopmental problems.

 

Source:Nature