Scientists Coax Stem Cells to Form 3D Mini Lungs

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Newswise ANN ARBOR, Mich. Scientists have coaxed stem cells to grow the first three-dimensional mini lungs.

Previous research has focused on deriving lung tissue from flat cell systems or growing cells onto scaffolds made from donated organs. In a study published in the online journal eLife the multi-institution team defined the system for generating the self-organizing human lung organoids, 3D structures that mimic the structure and complexity of human lungs.

These mini lungs can mimic the responses of real tissues and will be a good model to study how organs form, change with disease, and how they might respond to new drugs, says senior study author Jason R. Spence, Ph.D., assistant professor of internal medicine and cell and developmental biology at the University of Michigan Medical School.

The scientists succeeded in growing structures resembling both the large airways known as bronchi and small lung sacs called alveoli.

Since the mini lung structures were developed in a dish, they lack several components of the human lung, including blood vessels, which are a critical component of gas exchange during breathing.

Still, the organoids may serve as a discovery tool for researchers as they churn basic science ideas into clinical innovations. A practical solution lies in using the 3-D structures as a next step from, or complement to, animal research.

Cell behavior has traditionally been studied in the lab in 2-D situations where cells are grown in thin layers on cell-culture dishes. But most cells in the body exist in a three-dimensional environment as part of complex tissues and organs.

Researchers have been attempting to re-create these environments in the lab, successfully generating organoids that serve as models of the stomach, brain, liver and human intestine.

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Scientists Coax Stem Cells to Form 3D Mini Lungs

Scientists coax stem cells to form 3-D mini lungs

Human lung organoids will help scientists learn more about lung diseases, test new drugs

IMAGE:Scientists, led by the University of Michigan Medical School, coax stem cells to form mini lungs, 3-D structures that mimic human lungs and survived in the lab for 100 days.... view more

Credit: University of Michigan Health System

ANN ARBOR, Mich. - Scientists have coaxed stem cells to grow the first three-dimensional mini lungs.

Previous research has focused on deriving lung tissue from flat cell systems or growing cells onto scaffolds made from donated organs.

In a study published in the online journal eLife the multi-institution team defined the system for generating the self-organizing human lung organoids, 3D structures that mimic the structure and complexity of human lungs.

"These mini lungs can mimic the responses of real tissues and will be a good model to study how organs form, change with disease, and how they might respond to new drugs," says senior study author Jason R. Spence, Ph.D., assistant professor of internal medicine and cell and developmental biology at the University of Michigan Medical School.

The scientists succeeded in growing structures resembling both the large airways known as bronchi and small lung sacs called alveoli.

Since the mini lung structures were developed in a dish, they lack several components of the human lung, including blood vessels, which are a critical component of gas exchange during breathing.

Still, the organoids may serve as a discovery tool for researchers as they churn basic science ideas into clinical innovations. A practical solution lies in using the 3-D structures as a next step from, or complement to, animal research.

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Scientists coax stem cells to form 3-D mini lungs

The Society for Brain Mapping and Therapeutics (SBMT) hits its high notes for its 12th Annual meeting bringing Los …

LOS ANGELES, March 23, 2015 /PRNewswire-USNewswire/ -- World leading scientists gathered at the LA Convention Center from March 6-8 for a marathon scientific presentation. 600 presentations in 110 scientific sessions covered recent advances in ALS, Parkinson's Disease, Alzheimer's Disease, brain cancers, spine disorders, psychiatric disorders, autism, depression, PTSD, schizophrenia, multiple sclerosis, brain trauma, space medicine, epilepsy, vascular disorders, stroke, stem cell, neuro-mathematics, bio-material and tissue engineering, multi-modality imaging, epigenetic and genomic of brain disorders, brain bionics, minimally invasive therapy, focus ultrasound, microgravity, supercomputing and big-data, virtual reality medicine, NIH and DARPA funding, nanoneuroscience and nanoneurosurgery, neurovascular disorders, biomarkers, pediatric neurosurgery, dementia, brain bank, brain ablation, Neuro-ophthalmology, neuro-oncology, radiation physics, neurophotonics, peripheral never therapy, deep brain stimulation, brain health and fitness, NASA technologies, Los Alamos National Lab and brain policy and ethics. Winthrop University Hospital designates this world class scientific program for a maximum of 13.5 AMA PRA category 1 CME credits.

The preparation for the program started 18 months ago including near 100 members of the scientific program committee from 50 universities and near 40 scientists from NASA and Los Alamos National Lab presenting their advanced technologies at the meeting. The Honorable Congressman Chaka Fattah delivered the opening keynote at the LA Convention Center stating that "you would not find this type of diversity geographically and otherwise in any other great organizations that are gathering."

The annual SBMT World Congress is a multidisciplinary forum designed to facilitate cross-disciplinary dissemination of technological and medical advances and scientific discovery. The SBMT World congress has brought together neurosurgeons, radiologists, neurologists, neuro-oncologists, psychiatrists, bioethicists, policy makers, government officials, engineers, physicists, computer scientists, neuroscientists, allied healthcare professionals, healthcare executives, students, post-docs, residents and fellows. SBMT's annual meetings are world class scientific events designed to have a significant impact on cross-disciplinary flow of information and scientific advancements.

"We had the largest numbers of keynote and presenters in this convention, which was truly started as an spinoff collaboration between me and Dr. Kateb 13 years ago with 10 speakers and few people in the audience; since then we have published numerous papers showing latest technology could indeed helpful in diagnosis and treatment of neurological disorders and now we have ongoing clinical trials," said Dr. Shouleh Nikzad, immediate past President of SBMT, Senior Research Scientist, Principal Member of Staff, Technical Supervisor and Lead, Advanced UV/Vis/NIR Detector Arrays and Imaging Systems, and Nanoscience Group, Lead, Strategic Initiative on Gigapixel Focal Plane Arrays, Deputy Lead, Advanced Imaging Systems, NASA's Jet Propulsion Laboratory, California Institute of Technology.

In recent years, astonishing advances have contributed to amazing discoveries and breakthroughs in fields of neurology, neuroscience, neurosurgery, radiology, engineering, computer science, nanotechnology, medical imaging, medical devices and cellular/stem cell therapy. These scientific advances also have contributed to the large gap of knowledge amongst the scientists in different disciplines. One of the major challenges of 21st century for the scientific community is how to close such gaps of knowledge amongst multiple disciplines. SBMT has designed and created G20 World Brain Mapping and Therapeutic Initiative and African Brain Mapping Initiative to address such challenges at the global level by bringing together world class experts across multiple disciplines.

"SBMT is now a global leader in brain mapping and therapeutics by introducing modern and game changing initiatives such as G20 and African Brain Mapping Initiative; The organization has been on the forefront of translational neuroscience," Said Dr. John Ouma, the new President of SBMT (2015-2016), Chairman of Neurosurgery at University of the Witwatersrand, Johannesburg.

This year's program had 10 keynote speakers including: Congressman Fattah, Dr./Rear Admiral Raquel Bono, Drs. Keith L. Black (Chairman of Neurosurgery at Cedars-Sinai Medical Center), Nancy Sauer (Deputy Director of Los Alamos National Lab), Jakob Van Zyl (Associate Director of Project Formulation-NASA/JPL), Michael W Weiner (Professor of Radiology, Medicine and Psychiatry at UCSF), Morteza Gharib (Vice Provost of Caltech), Jaimie Henderson (Professor of Neurology and Neurosurgery at Stanford University), Skip Rizzo (Director of Medical Virtual Reality at USC) and Douglas Davis (Vice President of Intel) as well as Mitch Berger (Chairman of Department of Neurosurgery at UCSF) who was the first Ferenc A. Jolesz Memorial lecturer.

The Society and the Brain Mapping Foundation annually award leaders, philanthropists and pioneers in the field were honored this year.

Professor Stephen Hawking (Beacon of Courage and Dedication Award) for his clear beacon status, for publicly and courageously living with ALS and monumentally contributing to our understanding of the universe and thereby raising public awareness about the ALS.

Professor Hawking said, "SBMT's approach is bold and innovative as it takes advantage of talents and diversity of approach in various disciplines"

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The Society for Brain Mapping and Therapeutics (SBMT) hits its high notes for its 12th Annual meeting bringing Los ...

Altering mechanical properties of cell environments to produce desired chemical outputs

6 hours ago by Denis Paiste MIT biological engineering graduate student Frances Liu works with a spiral-shaped inertial microfluidic separation device for separating stem cell populations in the Laboratory for Material Chemomechanics at MIT. This device was adapted from previous designs to separate cells as a function of diameter. Liu also grows bone marrow-derived stem cells and studies how those stem cells release certain chemicals in response to mechanical interactions with materials in the surrounding environment. Credit: Denis Paiste/Materials Processing Center

Researchers in MIT Associate Professor Krystyn J. Van Vliet's group last year showed that three biomechanical and biophysical markers could accurately identify the most desirable stem cells from a mixed group of bone marrow-derived cells. Now, MIT biological engineering graduate student Frances Liu is trying to advance that work by understanding how to alter the stem cells' physical environment to get them to produce the most desirable chemical output.

The bone marrow cells secrete special chemicals called cytokines that are needed in the body to repair bone tissue, fat tissue, and connective tissue like cartilage. "These so-called factors that the cells produce are associated with those tissue growth functions and tissue repair functions," Van Vliet says.

Liu grows bone marrow-derived stem cells and studies how those stem cells release certain chemicals in response to mechanical interactions with materials in their surrounding environment. "I would like to manipulate the cells, using cell-material interactions, or synthetic materials, to produce certain chemicals beneficial to tissue repair," Liu explains in the Laboratory for Material Chemomechanics at MIT. "Right now we are in the characterization phase, quantifying which and how much of different cytokines the cells secrete in response to different chemical and mechanical cues that we provide. Down the line, we aim to engineer those cytokine profiles using cell-material interactions." Liu, 24, is a third-year PhD student and expects to complete her doctorate in 2017. She received her bachelor of science degree in biomedical engineering from Brown University.

Liu is examining how various groups of stem cells differ in response to lab-controlled changes in their environment in ways that might be important for tissue repair in the body. "Frances is determining the correlations between the mechanical properties of the materials the cells interact with and the chemical factors that they produce in response to that chemomechanical coupling," Van Vliet says.

Heterogeneous cellular factories

"You can think of the cells as factories; they're factories of chemicals," Van Vliet explains. "One of the main ways you change the way that factory operates is you change the material properties of its environment. How stiff that environment is, how acidic that environment is, how rough that environment is, all of those characteristics of the cell's outside world can directly correlate with the chemicals that that cell produces. We don't really understand all of why that happens yet, but part of Frances' thesis is to understand these particular stem cells and the subpopulations within them."

While other researchers previously studied mechanical factors such as stiffness on the function of these mesenchymal (bone marrow-derived) stem cells, it wasn't widely recognized that they were examining a mixed population of cells, not a single well-defined cell population. "Some of them were stem cells, but some were not," Van Vliet says.

One way that Liu sorts her stem cells into groups is using an inertial microfluidic separation device that separates cells of large diameter cells from those of small diameter. This device was adapted from previous designs of their collaborator, MIT Professor Jongyoon Han, as part of the interdisciplinary team that Van Vliet leads within the Singapore-MIT Alliance for Research and Technology (SMART). The group showed in a 2014 paper that three markerssize, mechanical stiffness, and how much the nucleus inside the cell moves aroundare sufficient to identify stem cells in a heterogeneous population of chemically similar but non-stem cells. "We measured those three properties as well as several other properties, but only those three properties together, that triplet of properties, distinguished a stem cell from a non-stem cell," Van Vliet says.

By using the microfluidic device, we can better understand the differences between the subpopulations of these heterogeneous bone marrow cells and which cytokines each subpopulation may be secreting, both in the body and in the lab.

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Altering mechanical properties of cell environments to produce desired chemical outputs

New Drug May Help Keep Hodgkin Lymphoma at Bay

WEDNESDAY, March 18, 2015 (HealthDay News) -- An FDA-approved drug doubled the amount of time that patients with Hodgkins lymphoma survived without any progression in their disease, a new study shows.

All of the patients also received stem cell therapy along with the drug, called brentuximab vedotin.

While the results are encouraging, doctors may never know if the drug is actually lengthening patients' lives, said Dr. Owen O'Connor, director of the Center for Lymphoid Malignancies at Columbia University Medical Center in New York City.

That's because brentuximab is fast becoming standard care for all patients with Hodgkin lymphoma who've relapsed after stem cell transplant, he said. So, a trial comparing the survival of patients who got the drug against those who did not might never be feasible, due to ethical concerns.

O'Connor was not involved in the trial, which was led by Dr. Craig Moskowitz, professor of medicine at Memorial Sloan Kettering Cancer Center in New York City. His team published the findings March 18 in The Lancet. The study was funded by Seattle Genetics Inc. and drug maker Takeda.

According to the American Cancer Society, about 9,000 new cases of Hodgkin lymphoma are diagnosed each year, and more than 1,100 people die from the illness annually. The cancer most often strikes young adults.

The phase 3 trial of brentuximab vedotin included 329 patients, aged 18 and older, who were at high risk of cancer relapse or progression after undergoing stem cell transplant, in which healthy stem cells from the patient are used to replace those lost to cancer or chemotherapy.

The patients were randomly assigned to receive 16 cycles of brentuximab vedotin infusions once every three weeks, or an inactive placebo.

After two years, there was no cancer progression in 65 percent of the patients who received the drug, compared with 45 percent of those in the placebo group, the researchers found. Progression-free survival was 43 months for those who received the drug, compared with 24 months for those in the placebo group.

"Nearly all of these patients who are progression-free at two years are likely to be cured since relapse two years after a transplant is unlikely," Moskowitz said in a journal news release. "No medication available today has had such dramatic results in patients with hard-to-treat Hodgkin lymphoma," he said.

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New Drug May Help Keep Hodgkin Lymphoma at Bay

Wu Medical Center – A Leading Medical Center for Stem Cell …

WuMedical Center (WMC) was named after Dr. Like Wu, the co-Founder, Chief Neurologist and Managing Director of the center. Using the unique stem cell technologies innovated by Dr. Wu, since 2005, he and his medical team have successfully treated over 2,000 patients from all over the world suffering from various neurological diseases, disorders, and injuries including Parkinson's disease, post-stroke, Batten's disease, ALS, MS, MSA, PSP, cerebral palsy, traumatic brain and spinal cord injuries, etc. This has laid a solid foundation for the application of stem cell technologies to treat these previously untreatable neurological diseases.

To make a world of difference in the lives of patients and their families by integrating new medical technologies, care, education and research to provide the highest quality care and service to our diverse community.

WSCMC will be one of the best stem cells medical centers in the world, known for advancing research and providing definitive diagnosis and treatment for our diverse community of patients with complex neurological diseases.

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Wu Medical Center - A Leading Medical Center for Stem Cell ...

OSKM stoichiometry determines iPS cell reprogramming

13 hours ago (top) Adding 9 amino acids before Klf4 to switch the isoform from Klf4S to Klf4L subtly lengthens the transgene. (bottom left) This lengthening causes a significant increase in the Klf4 protein expression. (bottom right) It also increases the proportion of reprogrammed cells (green) to partially reprogrammed cells (red). Credit: Dr. Knut Woltjen's Laboratory

Researchers at Kyoto University's Center for iPS Cell Research and Application discover a simple way to increase the production of induced pluripotent stem cells. A major hurdle in reprogramming science is generating a sufficient number of iPS cells to conduct basic research experiments. Yet, a report published in Stem Cell Reports shows that simply adding 9 amino acids to the induction transgene Klf4 dramatically elevates the production of fully reprogrammed mouse iPS cells.

Anyone in the field of cell reprogramming recognizes Oct3/4, Sox2, Klf4, and c-Myc, or "OSKM", as the Yamanaka factors that led to the first iPS cells. Originally, these four genes were delivered as individual (monocistronic) viral vectors. In order to simplify protocols, researchers began to deliver them using single polycistronic vectors, where the OSKM genes are linked as mRNA but still produce four separate proteins to induce reprogramming. However, not all vectors are built the same, and it turns out their subtle variations may influence both reprogramming efficiencies and outcomes. Specifically, the length of Klf4 appears to be a significant factor in determining whether a somatic cell is reprogrammed to the pluripotent state. Klf4 was first reported in 1996 by two independent studies. However, despite investigating the same gene, those two reports predicted different locations of the start codon in the mRNA sequences, which when translated result in proteins that differ by nine amino acids in length. Which isoform is used for reprogramming depends on the lab. "Some labs use short Klf4, some labs use long. Some labs have even switched between the two lengths," says Knut Woltjen, Ph.D., Associate Professor at CiRA.

Curious if these amino acids could explain the diverse reprogramming efficiencies that have been reported by different labs, Woltjen and his team employed piggyBac transposons to deliver various polycistronic reprogramming factors, controlling for the Klf4 length. They found that transfection with polycistronic vectors carrying the shorter Klf4 (Klf4S) resulted in more cells that initiated reprogramming, but failed to complete it, leaving them as partially reprogrammed. In contrast, the majority of cells transfected with vectors carrying the longer Klf4 (Klf4L) became true iPS cells. Deeper investigation found that polycistronic vectors with the Klf4L isoform showed much higher Klf4 protein expression, suggesting that the stoichiometry of the reprogramming factors could be the critical factor underlying reprogramming efficiency. According to Woltjen, "The stoichiometry is so important. No matter what system you use to establish it, the stoichiometry has a major impact on the quality of iPS cells." Other studies have noted stoichiometry effects, but Woltjen's team is the first to propose variation in a single factor's mRNA sequence as a determining factor in establishing stoichiometry. Supporting their hypothesis, appending Klf4S with the missing nine amino acids switched the Klf4 expression and reprogramming dynamics to mirror those seen with Klf4L.

Moreover, these differences in stoichiometry were reflected in gene expression patterns observed during the reprogramming process. Although reprogramming with either Klf4S or Klf4L led to the activation of many hallmark reprogramming genes, the majority of gene regulation was clearly dissimilar. Studying the reprogramming process induced by eight different polycistronic vectors, the team observed that both reprogramming performance and gene expression bifurcated with the Klf4 isoform. This finding may suggest that for popular vectors containing Klf4S, a simple modification of the Klf4 length could augment the number of properly reprogrammed cells. For researchers studying the reprogramming process itself, such vector differences raise caution when directly comparing reprogramming data between labs.

Interestingly, the differences associated with Klf4 length appeared mainly when reprogramming with polycistronic vectors. If instead either Klf4S or Klf4L was induced using a monocistronic vector in combination with an OSM polycistronic vector, the isoform dependency of reprogramming disappeared. These results suggest that the polycistronic design of the vector has some innate effect on the expression level of Klf4, while the protein function itself may not be affected. Nevertheless, inappropriate ratios of monocistronic vectors could also lead to a similar stoichiometry effect. Shin-Il Kim, Ph.D., first author of the study, stresses that just recognizing OSKM is not enough when reprogramming and that one must also be aware of the relative expression of the four genes. "Initially, we had no idea how much of a difference it [the 9 amino acids] would make. It goes to show how important it is to really know the materials you are working with."

Explore further: Carcinogenic mechanism of incomplete cell reprogramming in vivo

More information: Shin-Il Kim, Fabian Oceguera-Yanez, Ryoko Hirohata, Sara Linker, Keisuke Okita, Yasuhiro Yamada, Takuya Yamamoto, Shinya Yamanaka, and Knut Woltjen. KLF4 N-Terminal Variance Modulates Induced Reprogramming to Pluripotency. Stem Cell Reports, 2015.

A research team led by the group of Professor Yasuhiro Yamada, Center for iPS Cell Research and Application (CiRA), Kyoto University, has discovered that when cells are subjected to incomplete reprogramming ...

Austin Smith and his research team at the Centre for Stem Cell Research in Cambridge have just published in the journal Development a new and safer way of generating pluripotent stem cells - the stem cells that can give r ...

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OSKM stoichiometry determines iPS cell reprogramming

New ALS gene and signaling pathways identified

IMAGE:Induced pluripotent stem cell-derived motor neurons from an ALS patient (left) compared with normal cells (right). The cells are being used to study the role of the genes TBK1 and... view more

NEW YORK, NY (February 19, 2015)--Using advanced DNA sequencing methods, researchers have identified a new gene that is associated with sporadic amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. ALS is a devastating neurodegenerative disorder that results in the loss of all voluntary movement and is fatal in the majority of cases. The next-generation genetic sequencing of the exomes (protein-coding portions) of 2,874 ALS patients and 6,405 controls represents the largest number of ALS patients to have been sequenced in a single study to date.

Though much is known about the genetic underpinnings of familial ALS, only a handful of genes have been definitively linked to sporadic ALS, which accounts for about 90 percent of all ALS cases. The newly associated gene, called TBK1, plays a key role at the intersection of two essential cellular pathways: inflammation (a reaction to injury or infection) and autophagy (a cellular process involved in the removal of damaged cellular components). The study, conducted by an international ALS consortium that includes scientists and clinicians from Columbia University Medical Center (CUMC), Biogen Idec, and HudsonAlpha Institute for Biotechnology, was published today in the online edition of Science.

"The identification of TBK1 is exciting for understanding ALS pathogenesis, especially since the inflammatory and autophagy pathways have been previously implicated in the disease," said Lucie Bruijn, PhD, Chief Scientist for The ALS Association. "The fact that TBK1 accounts for one percent of ALS adds significantly to our growing understanding of the genetic underpinnings of the disease. This study, which combines the efforts of over two dozen laboratories in six countries, also highlights the global and collaborative nature of ALS research today.

"This study shows us that large-scale genetic studies not only can work very well in ALS, but that they can help pinpoint key biological pathways relevant to ALS that then become the focus of targeted drug development efforts," said study co-leader David B. Goldstein, PhD, professor of genetics and development and director of the new Institute for Genomic Medicine at CUMC. "ALS is an incredibly diverse disease, caused by dozens of different genetic mutations, which we're only beginning to discover. The more of these mutations we identify, the better we can decipher--and influence--the pathways that lead to disease." The other co-leaders of the study are Richard M. Myers, PhD, president and scientific director of HudsonAlpha, and Tim Harris, PhD, DSc, Senior Vice President, Technology and Translational Sciences, Biogen Idec.

"These findings demonstrate the power of exome sequencing in the search for rare variants that predispose individuals to disease and in identifying potential points of intervention. We are following up by looking at the function of this pathway so that one day this research may benefit the patients living with ALS," said Dr. Harris. "The speed with which we were able to identify this pathway and begin our next phase of research shows the potential of novel, focused collaborations with the best academic scientists to advance our understanding of the molecular pathology of disease. This synergy is vital for both industry and the academic community, especially in the context of precision medicine and whole-genome sequencing."

"Industry and academia often do things together, but this is a perfect example of a large, complex project that required many parts, with equal contributions from Biogen Idec. Dr. Tim Harris, our collaborator there, and his team, as well as David Goldstein and his team, now at Columbia University, as well as our teams here at HudsonAlpha, said Dr. Myers. "I love this research model because it doesn't happen very frequently, and it really shows how industry, nonprofits, and academic laboratories can all work together for the betterment of humankind. The combination of those groups with a large number of the clinical collaborators who have been seeing patients with this disease for many years and providing clinical information, recruiting patients, as well as collecting DNA samples for us to do this study, were all critical to get this done."

Searching through the enormous database generated in the ALS study, Dr. Goldstein and his colleagues found several genes that appear to contribute to ALS, most notably TBK1 (TANK-Binding Kinase 1), which had not been detected in previous, smaller-scale studies. TBK1 mutations appeared in about 1 percent of the ALS patients--a large proportion in the context of a complex disease with multiple genetic components, according to Dr. Goldstein. The study also found that a gene called OPTN, previously thought to play a minor role in ALS, may actually be a major player in the disease.

"Remarkably, the TBK1 protein and optineurin, which is encoded by the OPTN gene, interact physically and functionally. Both proteins are required for the normal function of inflammatory and autophagy pathways, and now we have shown that mutations in either gene are associated with ALS," said Dr. Goldstein. "Thus there seems to be no question that aberrations in the pathways that require TBK1 and OPTN are important in some ALS patients."

The researchers are currently using patient-derived induced pluripotent embryonic stem cells (iPS cells) and mouse models with mutations in TBK1 or OPTN to study ALS disease mechanisms and to screen for drug candidates. Several compounds that affect TBK1 signaling have already been developed for use in cancer, where the gene is thought to play a role in tumor-cell survival.

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New ALS gene and signaling pathways identified

Human skin may harbor obesity cure

Researchers have recently converted human skin cells into appetite controlling neurons for the first time ever, which might eventually provide obesity cure.

The study, led by researchers at Columbia University Medical Center (CUMC) and at the New York Stem Cell Foundation (NYSCF), found that cells provided individualized model for studying obesity and testing treatments.

To make the neurons, human skin cells were first genetically reprogrammed to become induced pluripotent stem (iPS) cells. Like natural stem cells, iPS cells are capable of developing into any kind of adult cell when given a specific set of molecular signals in a specific order.

The iPS cell technology has been used to create a variety of adult human cell types, including insulin-producing beta cells and forebrain and motor neurons.

The CUMC/NYSCF team determined which signals are needed to transform iPS cells into arcuate hypothalamic neurons, a neuron subtype that regulates appetite. The transformation process took about 30 days.

The neurons were found to display key functional properties of mouse arcuate hypothalamic neurons, including the ability to accurately process and secrete specific neuropeptides and to respond to metabolic signals such as insulin and leptin.

The study is published in the Journal of Clinical Investigation. (ANI)

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Human skin may harbor obesity cure

Neurons Controlling Appetite Made From Skin Cells

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Newswise NEW YORK, NY (February 27, 2015) Researchers have for the first time successfully converted adult human skin cells into neurons of the type that regulate appetite, providing a patient-specific model for studying the neurophysiology of weight control and testing new therapies for obesity. The study, led by researchers at Columbia University Medical Center (CUMC) and at the New York Stem Cell Foundation (NYSCF), was published last month in the online issue of the Journal of Clinical Investigation.

In a separate study, which appeared in the February 10 issue of the journal Development, Kevin Eggan, PhD, Florian Merkle, and Alexander Schier of Harvard University have also succeeded in creating hypothalamic neurons from iPS cells. These neurons help to regulate behavioral and basic physiological functions in the human body, including, in addition to appetite, hypertension, sleep, mood, and some social disorders. The investigators at Columbia and Harvard shared ideas during the course of the research, and these studies are co-validating.

Mice are a good model for studying obesity in humans, but it would better to have human cells for testing. Unfortunately, the cells that regulate appetite are located in an inaccessible part of the brain, the hypothalamus. So, until now, weve had to make do with a mouse model or with human cells harvested at autopsy. This has greatly limited our ability to study fundamental aspects of human obesity, said senior author Rudolph L. Leibel, MD, the Christopher J. Murphy Memorial Professor of Diabetes Research, professor of pediatrics and medicine, and co-director of the Naomi Berrie Diabetes Center at CUMC.

To make the neurons, human skin cells were first genetically reprogrammed to become induced pluripotent stem (iPS) cells. Like natural stem cells, iPS cells are capable of developing into any kind of adult cell when given a specific set of molecular signals in a specific order. The iPS cell technology has been used to create a variety of adult human cell types, including insulin-producing beta cells and forebrain and motor neurons. But until now, no one has been able to figure out how to convert human iPS cells into hypothalamic neurons, said co-author Dieter Egli, PhD, assistant professor of pediatrics (in developmental cell biology), a member of the Naomi Berrie Diabetes Center, and a senior research fellow at NYSCF.

This is a wonderful example of several institutions coming together to collaborate and advance research in pursuit of new therapeutic interventions. The ability to make this type of neuron brings us one step closer to the development of new treatments for obesity, said Susan L. Solomon, CEO of NYSCF.

The CUMC/NYSCF team determined which signals are needed to transform iPS cells into arcuate hypothalamic neurons, a neuron subtype that regulates appetite. The transformation process took about 30 days. The neurons were found to display key functional properties of mouse arcuate hypothalamic neurons, including the ability to accurately process and secrete specific neuropeptides and to respond to metabolic signals such as insulin and leptin.

We dont think that these neurons are identical to natural hypothalamic neurons, but they are close and will still be useful for studying the neurophysiology of weight control, as well as molecular abnormalities that lead to obesity, said Dr. Leibel. In addition, the cells will allow us to evaluate potential obesity drugs in a way never before possible.

This shows, said Dr. Eggan, how improved understanding of stem cell biology is making an impact on our ability to study, understand, and eventually treat disorders of the nervous system. Because there are so few hypothalamic neurons of a given type, they have been notoriously difficult to study. The successful work by both groups shows that this problem has been cracked.

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Neurons Controlling Appetite Made From Skin Cells