Directly Reprogramming Gut Cells into Beta Cells to Treat Diabetes


Type 1 diabetes mellitus results from destruction of insulin-producing beta cells in the pancreas. Diabetics have to give themselves routine shots of insulin. The hope that stem cells offer is the production of cells that can replace the lost beta cells. “We are looking for ways to make new beta cells for these patients to one day replace daily insulin injections,” says Ben Stanger, MD, PhD, assistant professor of Medicine in the Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania.

Some diabetics have had beta cells from cadavers transplanted into their bodies to replace the missing beta cells. Such a procedure shows that replacement therapy is, in principle possible. Therefore, transplanting islet cells to restore normal blood sugar levels in type 1 diabetics could treat and even cure disease. Unfortunately, transplantable islet cells are in short supply, and stem cell-based approaches have a long way to go before they reach the clinic. However, Stanger and his colleagues have tried a different strategy for treating type 1 diabetes. “It’s a powerful idea that if you have the right combination of transcription factors you can make any cell into any other cell. It’s cellular alchemy,” comments Stanger.

New research from Stanger and a postdoctoral fellow in his laboratory, Yi-Ju Chen that was published in Cell Reports, describes the production of new insulin-making cells in the gut of laboratory animals by introducing three new transcription factors. This experiment raises the prospect of using directly reprogrammed adult cells as a source for new beta cells.

In 2008, Stanger and others in Doug Melton’s laboratory used three beta-cell reprogramming factors (Pdx1, MafA, and Ngn3, collectively called PMN) to convert pancreatic acinar cells (the cells in the pancreas that secrete enzymes rather than hormones) into cells that had many of the features of pancreatic beta cells.

Following this report, the Stanger and his team set out to determine if other cells types could be directly reprogrammed into beta cells. “We expressed PMN in a wide spectrum of tissues in one-to-two-month-old mice,” says Stanger. “Three days later the mice died of hypoglycemia.” It was clear that Stanger and his crew were on to something. Further work showed that some of the mouse cells were making way too much extra insulin and that killed the mice.

When the dead mice were autopsied, “we saw transient expression of the three factors in crypt cells of the intestine near the pancreas,” explained Stanger.

They dubbed these beta-like, transformed cells “neoislet” cells. These neoislet cells express insulin and show outward structural features akin to beta cells. These neoislets also respond to glucose and release insulin when exposed to glucose. The cells were also able to improve hyperglycemia in diabetic mice.

Stanger and his co-workers also figured out how to turn on the expression of PMN in only the intestinal crypt cells to prevent the deadly whole-body hypoglycemia side effect that first killed the mice.

In culture, the expression of PMN in human intestinal ‘‘organoids,’ which are miniature intestinal units grown in culture, also converted intestinal epithelial cells into beta-like cells.

“Our results demonstrate that the intestine could be an accessible and abundant source of functional insulin-producing cells,” says Stanger. “Our ultimate goal is to obtain epithelial cells from diabetes patients who have had endoscopies, expand these cells, add PMN to them to make beta-like cells, and then give them back to the patient as an alternate therapy. There is a long way to go for this to be possible, including improving the functional properties of the cells, so that they more closely resemble beta cells, and figuring out alternate ways of converting intestinal cells to beta-like cells without gene therapy.”

This is hopefully a grand start to what might be a cure for type 1 diabetes.

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Pluristem’s Phase I/II Muscle Injury Trial Shows that Placental Stem Cells Augment Muscle Healing After Surgery


Pluristem Therapeutics Inc. a leading developer of placenta-based cell therapies, has announced top-line results from its Phase I/II clinical trial that accesses the safety and efficacy of PLacental eXpanded (PLX-PAD) cells in the treatment of muscle injury. This clinical trial showed that PLX-PAD cells were safe and effective. These results provide evidence that PLX cells may be efficacious in the treatment of orthopedic injuries including muscles and tendons.

This Phase I/II trial was a randomized, placebo-controlled, double-blinded study conducted at the Orthopedic Clinic of the Charité University Medical School under the auspices of the Paul-Ehrlich-Institute (PEI), Germany’s health authority. The injured muscle studied was the gluteus medius muscle in the buttock. Hip-replacement patients undergo a surgical procedure that injuries the gluteus medius muscle healing of this muscle after hip replacement surgery is crucial for joint stability and function.

Gluteal Muscles

The 20 patients in the study were randomized into three treatment groups. Each patient received an injection in the gluteal muscle that had been traumatized during surgery. One group was treated with 150 million PLX-PAD cells per dose (n=7), the second was administered 300 million PLX-PAD cells per dose (n=6), and the third received placebo (n=7).

The primary safety endpoint was clearly met since no serious adverse events were reported at either dose level. The study showed that PLX-PAD cells were safe and well tolerated.

The primary efficacy endpoint of the study (how well the stem cells worked) was the change in maximal voluntary isometric contraction force of the gluteal muscle at six months after surgery. Efficacy was shown in both PLX-PAD-treated patient groups. The group that received a dose of 150 million cells showed a statistically significant 500% improvement over the placebo group in the change of the maximal contraction force of the gluteal muscle (p=0.0067). Patients who received the lower dose (300 million cells) showed a 300% improvement over the placebo (p=0.18).

An analysis of the overall structure of the gluteal muscle using magnetic resonance imaging (MRI) indicated an increase in muscle volume in those patients treated with PLX-PAD cells versus the placebo group. The patients who had received the 150 million cell dose displayed a statistically significant superiority over the placebo group. Patients treated at the 150 million cell dose showed an approximate 300% improvement over the placebo in the analysis of muscle volume (p=0.004). Patients treated at the 300 million cell dose showed an approximate 150% improvement over the placebo in the change of muscle volume (p=0.19).

The study’s Senior Scientist, Dr. Tobias Winkler of the Center for Musculoskeletal Surgery, Julius Wolff Institute Berlin, Charité – Universitaetsmedizin Berlin, Germany, commented, “I am very impressed with the magnitude of the efficacy results seen in this trial. PLX cells demonstrated safety and suggested that the increase in muscle volume could be a mechanism for the improvement of contraction force.”

Zami Aberman Chairman and CEO stated, “This was a very important study not only for Pluristem but for the cell therapy industry in general. The study confirms our pre-clinical findings that PLX-PAD cell therapy can be effective in treating muscle injury. Having a statistically significant result for our primary efficacy endpoint is very encouraging and consistent with our understanding of the mechanism of action associated with cell therapy. Based on these results, we intend to move forward with implementing our strategy towards using PLX cells in orthopedic indications and muscle trauma.”

Placenta-Based Stem Cells Increasing Healing of Damaged Tendons in Laboratory Animals


Pluristem Therapuetics, a regenerative therapy company based in Haifa, Israel, has used placenta-based stem cells to treat animal with tendon damage, and the results of this preclinical study were announced at a poster presentation at the American Academy of Orthopedic Surgeons’ (AAOS) annual meeting in New Orleans.

Dr. Scott Rodeo of New York’s Hospital for Special Surgery (HSS) is the principal investigator for this preclinical trial. His poster session showed placental-based stem cells that were grown in culture and applied to damaged tendons seemed to have an early beneficial effect on tendon healing. In this experiment, animal tendons were injured by treatments with the enzyme collagenase. This enzyme degrades tendon-specific molecules and generates tendon damage, which provides an excellent model for tendon damage in laboratory animals. These placenta-based cells are not rejected by the immune system and can also be efficiently expanded in culture. The potential for “off-the-shelf” use of these cells is attractive but additional preclinical studies are necessary to understand how these cells actually help heal damaged tendons and affect tendon repair.

“Although our findings should be considered preliminary, adherent stromal cells derived from human placenta appear promising as a readily available cell source to aid tendon healing and regeneration,” stated Dr. Rodeo.

“These detailed preclinical results, as well as the favorable top-line results we announced from our Phase I/II muscle injury study in January, both validate our strategy to pursue advanced clinical studies of our PLX cells for the sports and orthopedic market,” stated Pluristem CEO Zami Aberman.

Dr. Rodeo and his orthopedic research team at HSS studied the effects of PLX-PAD cells, which stands for PLacental eXpanded cells in a preclinical model of tendons around the knee that had sustained collagenase-induced injuries. Favorable results from the study were announced by Pluristem on August 14, 2013. Interestingly, Dr. Rodeo, the Principal Investigator for this study is Professor of Orthopedic Surgery at Weill Cornell Medical College; Co-Chief of the Sports Medicine and Shoulder Service at HSS; Associate Team Physician for the New York Giants Football Team; and Physician for the U.S.A. Olympic Swim Team.