Stem Cell Clinic

University of Michigan Stem Cell Research | Overview

The University of Michigan has recently emerged as a national leader in the three main types of stem cell research: embryonic, adult, and reprogrammed cells known as iPS cells.

A long-time leader in the study of adult stem cells, U-M has bolstered its human embryonic stem cell program, and added a complementary iPS cell research effort, since the passage of Proposal 2 in November 2008. The state constitutional amendment eased onerous restrictions on the types of embryonic stem cell research allowed in Michigan.

Recent milestones include:

In addition to the work underway by the Consortium for Stem Cell Therapies, hubs for U-M stem cell research also exist at the Life Science Institutes Center for Stem Cell Biology and at the U-M Health Systems Comprehensive Cancer Center. Other groundbreaking stem cell work is being pursued at other units across campus.

The Center for Stem Cell Biology was established in 2005 with $10.5 million provided by the U-M Medical School, the Life Sciences Institute, and the Molecular and Behavioral Neurosciences Institute.

The centers main goal is to determine the fundamental mechanisms that regulate stem cell function. That knowledge, in turn, provides new insights into the origins of disease and suggests new approaches to disease treatment. Most of the work involves adult stem cells including blood-forming and nervous system stem cells but human embryonic stem cells also are studied.

The U-M Comprehensive Cancer Center is one of the few places in North America that has made an institutional commitment to cancer stem cell research. Cancer stem cells are responsible for triggering the uncontrolled cell growth that leads to malignant tumors.

U-M researchers were the first to identify stem cells in solid tumors, finding them in breast cancer in 2003. They were also the first to find pancreatic and head-and-neck stem cells. At the U-M cancer center, scientists are investigating how these cells mutate, causing unregulated growth that ultimately leads to cancer.

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University of Michigan Stem Cell Research | Overview

Stem Cells Successfully Transplanted And Grown In Pigs

June 5, 2014

Nathan Hurst, University of Missouri

One of the biggest challenges for medical researchers studying the effectiveness of stem cell therapies is that transplants or grafts of cells are often rejected by the hosts. This rejection can render experiments useless, making research into potentially life-saving treatments a long and difficult process. Now, researchers at the University of Missouri have shown that a new line of genetically modified pigs will host transplanted cells without the risk of rejection.

The rejection of transplants and grafts by host bodies is a huge hurdle for medical researchers, said R. Michael Roberts, Curators Professor of Animal Science and Biochemistry and a researcher in the Bond Life Sciences Center. By establishing that these pigs will support transplants without the fear of rejection, we can move stem cell therapy research forward at a quicker pace.

In a published study, the team of researchers implanted human pluripotent stem cells in a special line of pigs developed by Randall Prather, an MU Curators Professor of reproductive physiology. Prather specifically created the pigs with immune systems that allow the pigs to accept all transplants or grafts without rejection. Once the scientists implanted the cells, the pigs did not reject the stem cells and the cells thrived. Prather says achieving this success with pigs is notable because pigs are much closer to humans than many other test animals.

Many medical researchers prefer conducting studies with pigs because they are more anatomically similar to humans than other animals, such as mice and rats, Prather said. Physically, pigs are much closer to the size and scale of humans than other animals, and they respond to health threats similarly. This means that research in pigs is more likely to have results similar to those in humans for many different tests and treatments.

Now that we know that human stem cells can thrive in these pigs, a door has been opened for new and exciting research by scientists around the world, Roberts said. Hopefully this means that we are one step closer to therapies and treatments for a number of debilitating human diseases.

Roberts and Prather published their study, Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency in the Proceedings of the National Academy of Sciences.

Source: Nathan Hurst, University of Missouri

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Stem Cells Successfully Transplanted And Grown In Pigs

Cancer Centers Combine Expertise To Optimize Advanced Immunotherapy Strategies

Washington /PRNewswire/ - Physician researchers from Georgetown Lombardi Comprehensive Cancer Center, in Washington, D.C., and John Theurer Cancer Center (JTCC) in Hackensack, New Jersey, announce today the formation of the Regional Immunotherapy Discovery Program.

The Regional Immunotherapy Discovery Program will accelerate discovery and implementation of a new immunotherapy approach, which combines the full potential of two potent strategies currently used in treating cancer: cancer immunotherapy and bone marrow stem cell transplantation.

"We are at the dawn of an exciting new era," explains Louis M. Weiner, MD, director of Georgetown Lombardi. "The future of successful cancer therapy will rely heavily upon immunotherapythe power of the immune system to recognize and destroy malignant cells, and then to remember and eliminate cancers that try to recur."

Georgetown Lombardi, part of Georgetown University Medical Center and MedStar Georgetown University Hospital, and JTCC, part of Hackensack University Medical Center, already offer the most advanced clinical trials available using investigational immunotherapy drugs. And both offer transplant programs that manipulate the immune cells via both allogeneic (donor) and autologous (patient) transplants to treat patients with blood cancers.

"By combining these two strategies in attacking cancer, we believe it's possible to optimize the true promise of immunotherapy and extend treatment options to specific patient populations," says Andr Goy, MD, MS, chairman of JTCC. "This approach is only now emerging at a very limited number of cancer centers in the U.S."

One example of the new strategy would be to combine an immunotherapy drug such as a PD-1 inhibitor, which selectively unleashes immune cells, with an adoptive cellular therapy to assist reconstitution of the immune system following immune cell-depleting chemotherapy. This strategy is designed to deliver an overwhelming blow against a blood cancer.

In addition to the therapeutic impact, the Regional Immunotherapy Discovery Program has broad regional accessibility via physician researchers from Georgetown Lombardi in Washington, the MedStar Georgetown Cancer Network in Maryland and Washington, Regional Cancer Care Associates (RCCA) with offices throughout New Jersey, and JTTC in Hackensack. This means cancer patients living in the northeast corridor between Washington and the New York metropolitan area will have easy access to state-of-the-art immunotherapy clinical trials and care.

Michael B. Atkins, MD, an internationally recognized expert in immunotherapy and deputy director of Georgetown Lombardi, and Andrew L. Pecora, MD, president of RCCA, will lead the program, which builds on an oncology affiliation that Georgetown Lombardi, a National Cancer Institute (NCI) designated-comprehensive cancer center, and JTCC established in 2013. As part of the affiliation, the two institutions are working toward becoming an NCI-recognized consortium center, in which investigators from separate but collaborating scientific institutions contribute actively to the development and actualization of a specific cancer research agenda.

About John Theurer Cancer Center at Hackensack University Medical Center John Theurer Cancer Center at Hackensack UMC is among the nation's top 50 U.S. News & World Report Best Hospitals for cancer the highest-ranked inNew Jersey with this designation. It is ;New Jersey's largest and most comprehensive cancer center dedicated to the diagnosis, treatment, management, research, screenings, preventive care, as well as survivorship of patients with all types of cancer.

Each year, more people in the New Jersey/New York metropolitan area turn to the John Theurer Cancer Center for cancer care than to any other facility in New Jersey. The 14 specialized divisions feature a team of medical, research, nursing, and support staff with specialized expertise that translates into more advanced, focused care for all patients. The John Theurer Cancer Center provides comprehensive multidisciplinary care, state of the art technology, access to clinical trials, compassionate care and medical expertiseall under one roof. Physicians at the John Theurer Cancer Center are members of Regional Cancer Care Associates one of the nation's largest professional hematology/oncology groups. For more information please visit jtcancercenter.org.

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Cancer Centers Combine Expertise To Optimize Advanced Immunotherapy Strategies

Future heat stroke treatment found in dental pulp stem cells

PUBLIC RELEASE DATE:

5-Jun-2014

Contact: Robert Miranda cogcomm@aol.com Cell Transplantation Center of Excellence for Aging and Brain Repair

Putnam Valley, NY. (June 5, 2014) Scientists in Taiwan have found that intravenous injections of stem cells derived from human exfoliated deciduous tooth pulp (SHED) have a protective effect against brain damage from heat stroke in mice. Their finding was safe and effective and so may be a candidate for successfully treating human patients by preventing the neurological damage caused by heat stroke.

The study is published in a future issue of Cell Transplantation and is currently freely available on-line as an unedited early e-pub at: http://www.ingentaconnect.com/content/cog/ct/pre-prints/content-CT1100Tseng.

"Heat stroke deaths are increasing worldwide and heat stroke-induced brain injury is the third largest cause of mortality after cardiovascular disease and traumatic brain injury," said study lead author Dr. Ying-Chu Lin of the Kaohsiung Medical University School of Dentistry, Kaohsiung City, Taiwan. "Heat stroke is characterized by hyperthermia, systemic inflammatory response, multiple organ failure and brain dysfunction."

To investigate the beneficial and potentially therapeutic effects afforded by the protective activities of self-renewing stem cells derived from human exfoliated deciduous teeth, the scientists transplanted SHED into mice that had suffered experimental heat stroke.

According to the research team, these cells have "significantly higher proliferation rates" than stem cells from bone marrow and have the added advantages of being easy to harvest and express several growth factors, including vascular endothelial growth factor (VEGF), and they can promote the migration and differentiation of neuronal progenitor cells (NPCs).

"We observed that the intravenous administration of SHED immediately post-heat stroke exhibited several therapeutic benefits," said Dr. Lin. "These included the inhibition of neurological deficits and a reduction in oxidative damage to the brain. We suspect that the protective effect of SHED may be related to a decreased inflammatory response, decreased oxidative stress and an increase in hypothalamo-pituitary-adrenocortical axis activity following the heat stroke injury."

There are currently some drawbacks to the experimental therapy, said the researchers. First, there is a limited supply of SHED. Also, SHED transplantation has been associated with cancer and immune rejection.

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Future heat stroke treatment found in dental pulp stem cells

How planarians maintain their stem cell pools over generations

6 hours ago Fig. 1: Pluripotent stem cells enable planarians to achieve extraordinary feats of regeneration. (A) Planarians are able to re-grow an entire head in a matter of a few days. (B) The stem cells and their early offspring can be found almost all over the worms body. During regeneration, when a lot of new tissue has to be produced, they are able to generate a wide variety of cell types. The cell nuclei are marked in blue. Tissue-specific markers are marked in red, green and white. Credit: Max Planck Institute for Molecular Biomedicine /Bartscherer

Planarians are known as masters of regeneration: they can re-build any part of their bodies after amputation. This ability relies on a large number of pluripotent stem cells. To further investigate the mechanisms that enable planarians to maintain their stem cell pool over generations, scientists have now established a method for analysing the composition of planarian stem cells and the turnover of their proteins. They discovered a protein that is not only required for the maintenance of the stem cell pool in planarians, but might also be active in the pluripotent stem cells of mammals.

Of earthworms and flatworms

Everyone knows the myth about earthworms: if you cut them in half, you get two worms. Nothing could be further from the truth, alas. However, if the earthworm is replaced by a flatworm, the two parts can survive these childish experiments. What's more, be it skin, intestine or brain, the body part lost through cutting will simply grow again in a matter of days. The creatures involved here are planarians[1], a class of flatworms that are so flat that they need neither lungs nor a heart to take in and distribute oxygen in their bodies. So simple and yet so ingenious? It would appear so. Regeneration studies involving these animals have shown that a dismembered planarian can generate several hundred tiny animals, hence they could "almost be called immortal under the edge of a knife" (Dalyell, 1814). The astonishing aspect here is that both the blueprint and construction material for the regeneration process must be contained in each of the fragments: a small piece of tail, for example, becomes a complete worm under the animal's own strength and using existing resources.

Not the preserve of youth: pluripotency also available in adults

So where do the components needed to rebuild the cellular structures come from? In their search for the answer to this question, scientists have a population of small cells in their sights, namely the approximately five-micrometre-long neoblasts. These cells are found almost everywhere in the planarian body and behave like stem cells: they divide, renew and can form the different cell types that have been lost as a result of amputation (Fig. 1). When the planarian loses a body part or discards its tail for reproduction, the neoblasts are reactivated and migrate to the wound. They divide there and their offspring form a blastema, in which as a result of interplay between various extra- and intra-cellular factors important differentiation and patterning processes take place. Thanks to these processes, in turn, complex structures like the brain are formed. If the neoblasts are eliminated through radiation, for example, the planarian loses its ability to regenerate and dies within a few weeks. The fact that, following transplantation into an irradiated, neoblast-free worm, a single neoblast can produce all cell types and enable the host worm to regain its ability to regenerate shows that at least some neoblasts are pluripotent [2]. In healthy mammals, pluripotency, that is the ability of one cell to produce any given cell type found in an organism, e.g. muscle, nerve or pancreas cells, only arises in the early embryonic stage. Therefore, stable pluripotency in the adult organism is something special but not impossible as long as mechanisms exist for conserving this characteristic as is clearly the case with the planarians.

An in-vivo Petri dish for pluripotent stem cells

The preservation of pluripotency has been an important topic in stem cell research for years, and has mostly been examined up to now using isolated embryonic stem cells. Important transcription factors that can induce and preserve pluripotency were discovered in the course of this research. So what can planarians contribute to the current research if their stem cells cannot be cultivated and reproduced outside of the body? This is precisely where the strength of the planarians as a model system in stem cell research lies: the combination they can offer of a natural extracellular environment and pluripotent stem cells. Whereas cultivated stem cells are normally taken out of their natural environment and all important interactions with neighbouring cells and freely moving molecules are interrupted as a result, the stem cells in planarians can be observed and manipulated under normal conditions in vivo. Therefore, planarians are of interest as "in-vivo Petri dishes" for stem cells, in which not only their mechanisms for preserving pluripotency can be studied, but also their regulation and contribution to regeneration.

A venerable old worm meets ultra-modern next-generation technologies

Although planarians have been renowned as masters of regeneration and research objects for generations, they have undergone a genuine explosion in research interest in recent years. In particular, the possibility of switching off specific genes through RNA interference (RNAi) and the availability of the genome sequence of Schmidtea mediterranea, a planarian species which is especially good at regenerating itself, have contributed to this surge in interest. With the development of modern sequencing procedures, that is 'next generation sequencing', gene expression profiles that provide information about the specific genes activated in particular cells or tissues at particular points in time can now be produced on a large scale. Hence, it is possible to examine which messenger RNAs (mRNAs) are produced that act as molecular templates for the production of proteins. For example, hundreds of these mRNAs are produced after the amputation of a worm's head and their proteins provide potential regulators of the regeneration process [3; 4]. However, the real work only starts here: the extent to which the presence of a particular mRNA also reflects the volume of protein that is active in the cell remains to be determined. It is mainly the proteins in the form of enzymes, signalling molecules and structural elements, and not their mRNAs, that ultimately control the majority of cellular processes. In addition, their production using mRNA templates and their lifetime are precisely regulated processes and the frequency with which an mRNA arises cannot provide any information about these processes. The time has come, therefore, to develop experimental approaches for planarians that extend beyond gene expression analysis and lend greater significance to the subsequent regulatory processes.

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How planarians maintain their stem cell pools over generations