SCIENTISTS GENERATE FIRST HUMAN TISSUE IN L AB WITH STEM CELLS

Scientists used pluripotent stem cells to generate functional, three-dimensional human stomach tissue in a laboratory -- creating an unprecedented tool for researching the development and diseases of an organ central to several public health crises, ranging from cancer to diabetes.

Scientists at Cincinnati Children's Hospital Medical Center report Oct. 29 in Nature they used human pluripotent stem cells -- which can become any cell type in the body -- to grow a miniature version of the stomach. In collaboration with researchers at the University of Cincinnati College of Medicine, they used laboratory generated mini-stomachs (called gastric organoids) to study infection by H. pylori bacteria, a major cause of peptic ulcer disease and stomach cancer.

This first-time molecular generation of 3D human gastric organoids (hGOs) presents new opportunities for drug discovery, modeling early stages of stomach cancer and studying some of the underpinnings of obesity related diabetes, according to Jim Wells, PhD, principal investigator and a scientist in the divisions of Developmental Biology and Endocrinology at Cincinnati Children's.

It also is the first time researchers have produced 3D human embryonic foregut -- a promising starting point for generating other foregut organ tissues like the lungs and pancreas, he said.

"Until this study, no one had generated gastric cells from human pluripotent stem cells (hPSCs)," Wells said. "In addition, we discovered how to promote formation of three-dimensional gastric tissue with complex architecture and cellular composition."

This is important because differences between species in the embryonic development and architecture of the adult stomach make mouse models less than optimal for studying human stomach development and disease, Wells added.

Researchers can use human gastric organoids as a new discovery tool to help unlock other secrets of the stomach, such as identifying biochemical processes in the gut that allow gastric-bypass patients to become diabetes-free soon after surgery before losing significant weight. Obesity fueled diabetes and metabolic syndrome are an exploding public health epidemic. Until now, a major challenge to addressing these and other medical conditions involving the stomach has been a relative lack of reliable laboratory modeling systems to accurately simulate human biology, Wells explained.

The key to growing human gastric organoids was to identify the steps involved in normal stomach formation during embryonic development. By manipulating these normal processes in a petri dish, the scientists were able to coax pluripotent stem cells toward becoming stomach. Over the course of a month, these steps resulted in the formation of 3D human gastric organoids that were about 3mm (1/10th of an inch) in diameter. Wells and his colleagues also used this approach to identify what drives normal stomach formation in humans with the goal of understanding what goes wrong when the stomach does not form correctly.

Along with study first author Kyle McCracken, an MD/PhD graduate student working in Wells' laboratory, and Yana Zavros, PhD, a researcher at UC's Department of Molecular and Cellular Physiology, the authors report they were impressed by how rapidly H. pylori bacteria infected stomach epithelial tissues.

Within 24 hours, the bacteria had triggered biochemical changes to the organ, according to McCracken. The human gastric organoids faithfully mimicked the early stages of gastric disease caused by the bacteria, including the activation of a cancer gene called c-Met and the rapid spread of infection in epithelial tissues.

Another significant part of the team's challenge has been the relative lack of previous research literature on how the human stomach develops, the authors said. Wells said the scientists had to use a combination of published work, as well as studies from his own lab, to answer a number of basic developmental questions about how the stomach forms. Over the course of two years, this approach of experimenting with different factors to drive the formation of the stomach eventually resulted in the formation of 3D human gastric tissues in the petri dish.

Wells emphasized importance of basic research for the eventual success of this project, adding, "This milestone would not have been possible if it hadn't been for previous studies from many other basic researchers on understanding embryonic organ development."

Stem Cell Injections For Nerve Pain

Today's post from eurekalert.org (see link below) could potentially be as important an announcement as any other so-called neuropathy breakthroughs of the last few years. if only it were as simple as the title suggests. One of the major causes of nerve pain is the disintegration or degeneration of the myelin protective sheath around nerves. As with electrical wiring, if the insulation material is damaged (in this case, myelin), the live wire is exposed, causing short-outs etc. Finding something that can repair myelin at the point of damage, would be a major discovery in the fight against neuropathic pain and other symptoms. This article suggests that they may have found exactly that and by simply injecting certain cells extracted from bone marrow, the myelin sheath can be restored, thus blocking off the cause of pain. Whoopee! However, now come the disclaimers! As always with this sort of news, we discover that the research is only at the lab animal testing stage and that this particular form of stem cell therapy is closer to theory than practical application. This means that once more hopes are raised but the reality is that we're still years away from practical treatments. Okay, we'd rather hear about good news in the research field than be kept in the dark but there should always be a subtitle in heavy print, warning the neuropathy patient that they shouldn't start planning to restore their full and busy lives just yet. It's the nature of the beast!
 

Stem cell injections improve diabetic neuropathy in animal models 
Public Release: 23-Jun-2015 Putnam Valley, NY. (June 23, 2015)

 Bone-marrow-derived mesenchymal cells promote blood vessel growth and re-myelination of peripheral nerves
 
Cell Transplantation Center of Excellence for Aging and Brain Repair

 - Diabetic neuropathy (DN) is a condition in which perpetually high blood sugar causes nerve damage, resulting in a myriad of symptoms such as numbness, reduced ability to detect painful stimuli, muscle weakness, pain, and muscle spasms. DN affects up to 60 percent of patients with diabetes, is often the cause of foot ulcers, and can ultimately result in amputations. There is no curative therapy for DN, but a recent study carried out by a team of researchers in the U.S. and Korea has found that laboratory animals modeled with DN can experience both angiogenesis (blood vessel growth) and nerve re-myelination following injections of mesenchymal stem cells derived from bone marrow (BM-MSCs).

Their study will be published in a future issue of Cell Transplantation and is currently freely available on-line as an unedited early e-pub at: http://ingentaconnect.com/content/cog/ct/pre-prints/content-CT-1386_Han_et_al

The researchers used mesenchymal stem cells, which can be easily isolated from a variety of sources, such as adipose (fat) tissues, tendons, peripheral blood, umbilical cord blood, and bone marrow. MSCs derived from bone marrow (BM-MSCs) have been among the most successfully transplanted cells, offering therapeutic benefits for a wide range of conditions, from serious burns to cardiovascular diseases, including heart attack and stroke.

In this study, laboratory rats modeled with diabetes were randomly assigned to BM-MSC or saline injection groups 12 weeks after the induction of diabetes. The non-diabetic control group of rats was age- and sex-matched. DN was confirmed by latency in nerve conduction velocity tests.

"We investigated whether local transplantation of BM-MSCs could attenuate or reverse experimental DN by modulating angiogenesis and restoring myelin, the electrically insulating substance surrounding nerves that is reduced by DN," said study co-author Dr. Young-sup Yoon, Professor at the Department of Medicine, Division of Cardiology at Emory University School of Medicine. "In this study we have provided the first evidence that intramuscular injected BM-MSCs migrate to nerves and can play a therapeutic role."

According to the researchers, their findings indicate that intramuscular injection of MSCs resulted in an increase of multiple angiogenic and neurotrophic factors associated with blood vessel growth and subsequently aided the survival of diabetic nerves, suggesting that BM-MSC transplantation restored both the myelin sheath and nerve cells in diabetic sciatic nerves.

"We identified several new mechanisms by which MSCs can improve DN," said the researchers. "First, we demonstrated that numerous engraftments migrated to and survived in the diabetic nerves. Second, we demonstrated a robust increase in vascularity. Third, we found the first evidence that MSCs can directly modulate re-myelination and axonal regeneration."

The researchers concluded that DN, for which there is no other therapeutic option, can be an "initial target for cell therapy" and that transplantation of BM- MSCs "represents a novel therapeutic option for treating DN."

"Currently, the only treatment options available for DN are palliative (focused on alleviating pain) in nature, or are directed at slowing the progression of the disease by tightly controlling blood sugar levels, "says Dr. John R. Sladek, Jr., Professor of Neurology, Pediatrics, and Neuroscience, Department of Neurology at the University of Colorado School of Medicine. "This study offers new insight into the benefits of cell therapy as a possible treatment option for a disease that significantly diminishes quality of life for diabetic patients. Safety and efficacy for human application must be evaluated to further determine the feasibility of BM-MSC transplantation for treatment of DN."

Contact: Dr. Young-sup Yoon, Professor of Medicine, Department of Medicine, Division of Cardiology, Emory University School of Medicine, 101 Woodruff Circle, WMB 3009, Atlanta, GA 30322, USA.
Phone: 404-727-8176
Email: yyoon5@emory.edu
Fax: 404-727-3988

Citation: Han, J. W.; Choi, D.; Lee, M. Y.; Huh, Y. H.; Yoon, Y-S. Bone marrow-derived mesenchymal stem cells improve diabetic neuropathy by direct modulation of both angiogenesis and myelination in peripheral nerves. Cell Transplant. Appeared or available on-line: May 13, 2015.

The Coeditors-in-chief for CELL TRANSPLANTATION are at the Diabetes Research Institute, University of Miami Miller School of Medicine and Center for Neuropsychiatry, China Medical University Hospital, TaiChung, Taiwan. Contact, Camillo Ricordi, MD at ricordi@miami.edu or Shinn-Zong Lin, MD, PhD at shinnzong@yahoo.com.tw or David Eve, PhD or Samantha Portis, MS, at celltransplantation@gmail.com

News release by Florida Science Communications http://www.sciencescribe.net

http://www.eurekalert.org/pub_releases/2015-06/ctco-sci062315.php

Neuropathy And Stem Cell treatment A Personal Account

Today's post from neuropathy.org (see link below) is a personal account of one lady's experiences with getting neuropathy. There is no link to HIV but as we all know, irrespective of the cause, our neuropathy journeys are very similar in terms of symptoms and treatment. It is especially interesting for those considering stem cell treatment but that option remains very limited, according to the skills available in your area and the extent of your insurance coverage.

More Than Hope
By Mary Busch 
 
Editor’s Note: Mary Busch—a patient in our neuropathy community—shares her on-going journey that started with a getting a diagnosis, a frustrating quest for effective therapies, and a ray of hope that came in the form of a clinical research study. We appreciate Mary’s contributions to moving the ball forward in neuropathy research, as well as her willingness to share her inspiring story!

Just ten years ago, I was a “regular mom”—working, taking care of my family and my home…and trying to squeeze in a few moments each day to stay in shape. Little did I know that an insidious neuropathy diagnosis was going to change my life forever.

After my husband Mike's company shut down in December 2003, he took up a job in Texas. We found ourselves relocating, leaving behind our family and friends and what we called home (Cincinnati, OH) for thirty-nine years. The first few months went by quickly: I was setting up a new home, making sure our kids adjusted, and looking for a new job…all of this was stressful—to say the least. It was during this time that I first noticed a "tingling" sensation in my fingers.

I’m sure you’ve felt it: the “tingling” when your hands get really cold or when you have your hands in one position for too long, you develop this "pins and needles" feeling. I didn’t really pay much attention to these symptoms because they were sporadic. But then it wouldn’t go away…and I began dropping things and I couldn’t explain it away (“Don’t mind me; I’m just a little clumsy today!”).

The "pins and needles" feeling was spreading to my toes and it was becoming more bothersome. So, I went to a primary care doctor for an evaluation. She didn’t seem all that concerned about the symptoms, but gave me a prescription anyway. For the first few days after I started this medication, I could not keep my eyes open. Even after consulting her about adjusting the dose, I just couldn’t shake the drowsiness. Since my doctor wasn’t too concerned, I stopped the medication and I ignored the symptoms. After all, I was a busy mom and life was calling--even through these seemingly benign and annoying symptoms.

In August 2004, I was eager to start my new job at Blanton Elementary School. The "pins and needles" feeling was still there, but I was functioning pretty much at a normal level. By November, however, I could no longer ignore the symptoms: the "pins and needles" had spread to my arms and legs, and it was accompanied by numbness and fatigue. This time I consulted a different primary care doctor who started testing me for simple things like vitamin deficiencies.

When I got back to Texas after our holiday season travel to Cincinnati, I realized that my symptoms were worse. I was staggering; I couldn’t lift my arms; and I was falling. It was the fall that had me landing on my face that made my doctor refer me to a neurologist.

My first thought--after researching my symptoms--was that I might have multiple sclerosis (MS). After many blood tests, EMGs, an MRI, and a spinal tap, I was diagnosed with CIDP (chronic inflammatory demyelinating polyneuropathy--an autoimmune form of neuropathy). I later found out I was lucky: for many in the neuropathy community, it takes years to get diagnosed and to have access to treatments. My neurologist, at the time, put me on high-dose steroids for the next year. Although my symptoms dramatically improved, the side effects (weight gain, swollen knee joints, hypertension…) were devastating. I was told my CIDP wouldn’t return after I completed the steroid treatment. My neurologist was right…I was symptom-free for about a year. But, then it all came back; this time, the CIDP affected every part of my body—not just my arms and legs. I had trouble swallowing, nerve pain, muscle twitching, and spasms. It also affected my voice, speech, and cognitive skills…the list of symptoms seemed endless. I knew I needed a second opinion. I sought out another neurologist, Dr. Anna Tseng, who reconfirmed the CIDP diagnosis. She started me on a loading dose of Intravenous immunoglobulin (IVIG) at an infusion center.

For the next six years, I went through many treatments. Intravenous immunoglobulin (IVIG) was the only treatment that seemed to stabilize my symptoms, but the side effects were awful. I had severe headaches, nausea, and vomiting. My infusions were slowed down to the lowest dose to help minimize the side effects. My life revolved around the four 8-hour-days a month being infused and the following week spent recovering from the side effects of IVIG treatment. I made several ER trips to treat the dehydration that resulted from extreme vomiting. I also developed aseptic meningitis. My school’s principal was wonderful through all of this, but I was taking more and more time off because of my health issues. I felt that with each CIDP relapse my baseline health was slowly deteriorating. It got to the point where I couldn't work anymore…this was one of the lowest points in my life because I loved my job.

I had trouble swallowing, nerve pain, muscle twitching, and spasms. It also affected my voice, speech, and cognitive skills...the list of symptoms seemed endless.
 
In 2010, we found ourselves relocating to Florida. I started working with Dr. Lara Katzin at the University of South Florida to manage my neuropathy. There was an instant connection…we worked patiently together to tweak my IVIG treatments over the next few months, but I continued to struggle with the side effects.

While on a family trip to Bryce Canyon in 2011, I felt well enough to do some hiking. But I paid for it after getting back home. I was tired and weak…I thought a few days of rest would help me recover. But by the end of the week, I couldn’t walk; I couldn’t get out of bed; I couldn’t shower or even go to the bathroom on my own. I felt completely distraught and humiliated that I was unable to care for myself or my family. I had to call my parents to come and help me with the basics while my husband was at work. I spent the next six months in and out of a wheelchair. I had a lot of time in that wheelchair to think about my uncertain future. Because I wasn’t tolerating standard therapies, I was ready to give up. It was at that point, I began researching other options.

I recently learned about The Neuropathy Association--this find probably saved my life. I joined the Association’s local support group (in Tampa, Florida) to help myself and learn from others who were living with neuropathy. I also learned about clinical research trials through the Association’s website...this is how I found Dr. Richard Burt (head of the Hematopoietic Stem Cell Transplantation in CIDP research trial at Northwestern University)--my miracle worker.

I spent a lot of time researching transplantations and all the possible complications from the procedure. I spent months on Stem Cell-Facebook pages reading about other patients’ experiences. Then in April 2012, I met Wendy Nash--a fellow Floridian--who was participating in the clinical research study that I was considering. Wendy shared her journey with me and invited me to see first-hand what she was going through.

After talking with Wendy in April 2012, I applied for the clinical research study. In June 2012, I went for an initial 3-day evaluation with Dr. Burt to reconfirm my diagnosis and to confirm I met the clinical study criteria. I was accepted into the clinical research study—and, for the first time, I had hope--hope that I could beat neuropathy.

In September 2012, I started the long transplant process at Northwestern Memorial Hospital in Chicago. The first part is pre-transplant testing (cardiac, pulmonary, chest x-ray, EKG, labs, etc.). It was an exhaustive list, but Dr. Burt and his transplant team were very thorough. They wanted to make sure my body could handle the stress of the transplant procedure. During my testing, they found a large cyst on my ovary. So, even before I began, I had to have the cyst (and my ovaries) removed. After a few weeks of rest, I went back to Chicago for the stem cell transplant.

I was scared even though I had done my research, but I knew I was in good hands. I was admitted for an initial mobilization chemo—to stimulate the bone marrow to start producing stem cells. I was released from the hospital the next day and soon began filgrastrim shots to further stimulate my bone marrow to rapidly produce stem cells. The goal was to make enough stem cells to spill out of my bone marrow and into my circulating blood for harvesting. Approximately 10 days later, my stem cells were harvested through a catheter in my neck by a procedure called apheresis (a process that spins blood and separates the stem cells from all the other parts of the blood). 

Now, I was ready for the main part of the stem cell transplant. Again, I was admitted to Northwestern Memorial Hospital in Chicago where I would stay for the remainder of the transplant. By this time, I was already losing my hair; so I shaved my head completely ... I thought it would upset me, but I was so focused on the next part of the chemo that it didn’t faze me at all. The next seven days were filled with chemo treatments. The chemo gave me headaches and made me nauseous, but the staff was really great about addressing these side effects.

Finally, the big day arrived: November 21st, 2012! My white blood counts were down to zero (Day 0--in the transplant world) and I would be getting my stem cells back. It was my “New Birthday!” My parents (my caregivers throughout my Chicago stay) and I had a little ceremony celebrating the occasion. I would like to tell you it was all uphill from there, but it wasn't: I developed a fever. Dr. Burt and his team were very proactive. They started me on antibiotics right away and took blood cultures. It turned out I didn’t have any infection. Some people just develop post-transplant fevers. I was still nauseous and I didn’t have an appetite to eat. Now, it was just a matter of waiting for my stem cells to engraft (or repopulate) my body with healthy cells. That happened 9 days later and I was able to go home. It was a grueling time, but I look back at it now and it really went by quickly. I've already had six months of my life back for that period of misery…I would do it again in a heartbeat!

The main reason I considered the clinical research study was to give myself a fighting chance…plus, it feels good to know I’m also contributing to research and I’m helping others along the way. Today, I still have pain and my nerves haven’t completely healed yet. My nerves may take years to heal, but I feel so much better. The constant fatigue is gone and I am walking two to three miles (yes miles!) several times a week.

Not everybody is accepted into a clinical research study and some health insurances will not cover it because the treatments are experimental. For me, participating in a clinical research study was the beginning of my future—one I could look forward to with optimism. Instead of planning for treatments every month, I am now planning vacations with my family. Most stem cell patients are treatment-free for years after the transplant. The doctors call it is a long-term remission, not a cure. Even if it is not forever, the hematopoietic stem cell transplant has bought me time ... time for research to catch up!

http://www.neuropathy.org/site/News2?page=NewsArticle&id=8488&news_iv_ctrl=1101

Muscular Stem Cells May Repair Nerve Damage

Today's post from sciencedaily.com (see link below) talks about a new development in stem cell therapy, which could lead to several breakthroughs in the treatment of nerve damage and neuropathy. In this case, stem cells from human muscle tissue were able to repair nerve damage and improve function in mice. This depends on the stem cells being implanted at the site of the nerve injury, which suggests that it will only be effective if the place of injury is identified. For many people with neuropathy, identifying where the nerve damage is in the body is a very difficult process. Nevertheless, scientists are now trying to work out how muscular stem cells can trigger repair in damaged nerves. Another case of 'watch this space' I'm afraid but an interesting one.

Stem cells from muscle can repair nerve damage after injury 
University of Pittsburgh Schools of the Health Sciences March 18, 2014

Summary:

Stem cells derived from human muscle tissue were able to repair nerve damage and restore function in an animal model of sciatic nerve injury. The findings suggest that cell therapy of certain nerve diseases, such as multiple sclerosis, might one day be feasible.

Stem cells derived from human muscle tissue were able to repair nerve damage and restore function in an animal model of sciatic nerve injury, according to researchers at the University of Pittsburgh School of Medicine. The findings, published online today in the Journal of Clinical Investigation, suggest that cell therapy of certain nerve diseases, such as multiple sclerosis, might one day be feasible.

To date, treatments for damage to peripheral nerves, which are the nerves outside the brain and spinal cord, have not been very successful, often leaving patients with impaired muscle control and sensation, pain and decreased function, said senior author Johnny Huard, Ph.D., professor of orthopaedic surgery, and Henry J. Mankin Chair in Orthopaedic Surgery Research, Pitt School of Medicine, and deputy director for cellular therapy, McGowan Institute for Regenerative Medicine.

"This study indicates that placing adult, human muscle-derived stem cells at the site of peripheral nerve injury can help heal the lesion," Dr. Huard said. "The stem cells were able to make non-neuronal support cells to promote regeneration of the damaged nerve fiber."

The researchers, led by Dr. Huard and Mitra Lavasani, Ph.D., first author and assistant professor of orthopaedic surgery, Pitt School of Medicine, cultured human muscle-derived stem/progenitor cells in a growth medium suitable for nerve cells. They found that, with prompting from specific nerve-growth factors, the stem cells could differentiate into neurons and glial support cells, including Schwann cells that form the myelin sheath around the axons of neurons to improve conduction of nerve impulses.

In mouse studies, the researchers injected human muscle-derived stem/progenitor cells into a quarter-inch defect they surgically created in the right sciatic nerve, which controls right leg movement. Six weeks later, the nerve had fully regenerated in stem-cell treated mice, while the untreated group had limited nerve regrowth and functionality. Twelve weeks later, treated mice were able to keep their treated and untreated legs balanced at the same level while being held vertically by their tails. When the treated mice ran through a special maze, analyses of their paw prints showed eventual restoration of gait. Treated and untreated mice experienced muscle atrophy, or loss, after nerve injury, but only the stem cell-treated animals had regained normal muscle mass by 72 weeks post-surgery.

"Even 12 weeks after the injury, the regenerated sciatic nerve looked and behaved like a normal nerve," Dr. Lavasani said. "This approach has great potential for not only acute nerve injury, but also conditions of chronic damage, such as diabetic neuropathy and multiple sclerosis."

Drs. Huard and Lavasani and the team are now trying to understand how the human muscle-derived stem/progenitor cells triggered injury repair, as well as developing delivery systems, such as gels, that could hold the cells in place at larger injury sites.

Story Source:

The above story is based on materials provided by University of Pittsburgh Schools of the Health Sciences. Note: Materials may be edited for content and length.

http://www.sciencedaily.com/releases/2014/03/140318190035.htm