Weill Cornell Medicine Team Creates Self-Renewing Hematopoietic Stem Cells for Transplantation – Cornell Chronicle

Researchers at Weill Cornell Medicine have discovered an innovative method to make an unlimited supply of healthy blood cells from the readily available cells that line blood vessels. This achievement marks the first time that any research group has generated such blood-forming stem cells.

This is a game-changing breakthrough that brings us closer not only to treat blood disorders, but also deciphering the complex biology of stem-cell self-renewal machinery, said senior author Dr. Shahin Rafii, director of the Ansary Stem Cell Institute, chief of the Division of Regenerative Medicine and the Arthur B. Belfer Professor at Weill Cornell Medicine.

This is exciting because it provides us with a path towards generating clinically useful quantities of normal stem cells for transplantation that may help us cure patients with genetic and acquired blood diseases, added co-senior author Dr. Joseph Scandura, an associate professor of medicine and scientific director of the Silver Myeloproliferative Neoplasms Center at Weill Cornell Medicine.

Hematopoietic stem cells (HSCs) are long-lasting cells that mature into all types of blood cells: white blood cells, red blood cells and platelets. Billions of circulating blood cells do not survive long in the body and must be continuously replenished. When this does not happen, severe blood diseases, such as anemia, bleeding or life-threatening infections, can occur. A special property of HSCs is that they can also self-renew to form more HSCs. This property allows just a few thousand HSCs to produce all of the blood cells a person has throughout ones life.

This image shows reprogrammed hematopoietic stem cells (green) that are arising from mouse cells. These stem cells are developing close to a group of cells, called the vascular niche cells (gray), which provides them with the nurturing factors necessary for the reprogramming.

Researchers have long hoped to find a way to make the body produce healthy HSCs in order to cure these diseases. But this has never been accomplished, in part because scientists have been unable to engineer a nurturing environment within which stem cells can convert into new, long-lasting cellsuntil now.

In a paper published May 17 in Nature, Dr. Rafii and his colleagues demonstrate a way to efficiently convert cells that line all blood vessels, called vascular endothelial cells, into abundant, fully functioning HSCs that can be transplanted to yield a lifetime supply of new, healthy blood cells. The research team also discovered that specialized types of endothelial cells serve as that nurturing environment, known as vascular niche cells, and they choreograph the new converted HSCs self-renewal. This finding may solve one of the most longstanding questions in regenerative and reproductive medicine: How do stem cells constantly replenish their supply?

The research team showed in a 2014 Nature study that converting adult human vascular endothelial cells into hematopoietic cells was feasible. However, the team was unable to prove that they had generated true HSCs because human HSCs function and regenerative potential can only be approximated by transplanting the cells into mice, which dont truly mimic human biology.

To address this issue, the team applied their conversion approach to mouse blood marrow transplant models that are endowed with normal immune function and where definitive evidence for HSC potential could rigorously tested. The researchers took vascular endothelial cells isolated from readily accessible adult mice organs and instructed them to overproduce certain proteins associated with blood stem-cell function. These reprogrammed cells were grown and multiplied in co-culture with the engineered vascular niche. The reprogrammed HSCs were then transplanted as single cells with their progenies into mice that had been irradiated to destroy all of their blood forming and immune systems, and then monitored to see whether or not they would self-renew and produce healthy blood cells.

Study co-authors, from left: Dr. Joseph Scandura, Dr. Raphael Lis, Dr. Jason Butler, Michael Poulos, Balvir Kunar Jr., Chaitanya R. Badwe, Koji Shido, Dr. Zev Rozenwaks, Jose-Gabriel Barcia-Duran, Dr. Shahin Rafii and Dr. Jenny Xiang. Not pictured: Charles Karrasch, David Redmond, Dr. Will Schachterle, Michael Ginsberg, Dr. Arash Rafii. Photo credit: Michael Gutkin.

In collaboration withDr. Olivier Elemento, associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, andDr. Jenny Xiang, the director of Genomics Services, Dr. Rafii and his team also showed that the reprogrammed HSCs and their differentiated progenies including white and redbloodscells, as well as the immune cells were endowed with the same genetic attributes to that of normal adult stem cells. These findings suggest that the reprogramming process results in the generation of true HSCs that havegeneticsignature thatarevery similar to normal adult HSCs.Remarkably, the conversion procedure yielded a plethora of transplantable HSCs that regenerated the entire blood system in mice for the duration of their lifespans, a phenomenon known as engraftment. We developed a fully-functioning and long-lasting blood system, said lead authorDr. Raphael Lis, an instructor in medicine and reproductive medicine at Weill Cornell Medicine. In addition, the HSC-engrafted mice developed all of the working components of the immune systems. This is clinically important because the reprogrammed cells could be transplanted to allow patients to fight infections after marrow transplants, Dr. Lis said. The mice in the study went on to live normal-length lives and die natural deaths, with no sign of leukemia or any other blood disorders.

Study co-author Dr. Olivier Elemento. Photo credit: Roger Tully.

The Weill Cornell Medicine team is the first to achieve cellular reprogramming to create engraftable and authentic HSCs, which have been considered the holy grail of stem cell research. We think the difference is the vascular niche, said contributing authorDr. Jason Butler, an assistant professor of regenerative medicine at Weill Cornell Medicine. Growing stem cells in the vascular niche puts them back into context, where they come from and multiply. We think this is why we were able to get stem cells capable of self-renewing.

If this method can be scaled up and applied to humans, it could have wide-ranging clinical implications. It might allow us to provide healthy stem cells to patients who need bone marrow donors but have no genetic match, Dr. Scandura said. It could lead to new ways to cure leukemia, and may help us correct genetic defects that cause blood diseases like sickle-cell anemia.

More importantly, our vascular niche-stem-cell expansion model may be employed to clone the key unknown growth factors produced by this niche that are essential for self-perpetuation of stem cells, Dr. Rafii said. Identification of those factors could be important for unraveling the secrets of stem cells longevity and translating the potential of stem cell therapy to the clinical setting.

Additional study co-authors include Charles Karrasch, Dr. Michael Poulos, Balvir Kunar, David Redmond, Jose-Gabriel Barcia-Duran, Chaitanya Badwe, Koji Shido and Dr. Zev Rosenwaks of Weill Cornell Medicine; Dr. Will Schachterle, formerly of Weill Cornell Medicine, Dr. Arash Rafii of Weill Cornell Medicine-Qatar; Dr. Michael Ginsberg of Angiocrine Bioscience; and Dr. Nancy Speck of the Abramson Family Cancer Research Institute in the Perelman School of Medicine at the University of Pennsylvania.

Various study authors have relationships with Angiocrine Bioscience that are independent of Weill Cornell Medicine.

This study was funded in part by the National Institutes of Health, grants NIH-R01 DK095039, HL119872, HL128158, HL115128, HL099997, CA204308, HL133021, HL119872, HL128158 and HL091724; U54 CA163167; and NIH-T32 HD060600.

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Weill Cornell Medicine Team Creates Self-Renewing Hematopoietic Stem Cells for Transplantation - Cornell Chronicle

Injured bones reconstructed by gene and stem cell therapies – Medical Xpress

May 17, 2017 This illustration shows the bone-tissue engineering technique developed by Cedars-Sinai investigators. 'Endogenous MSCs' refers to stem cells from a patient's bone. The 'BMP gene' is a gene that promotes bone repair. Credit: Gazit Group/Cedars-Sinai

A Cedars-Sinai-led team of investigators has successfully repaired severe limb fractures in laboratory animals with an innovative technique that cues bone to regrow its own tissue. If found to be safe and effective in humans, the pioneering method of combining ultrasound, stem cell and gene therapies could eventually replace grafting as a way to mend severely broken bones.

"We are just at the beginning of a revolution in orthopedics," said Dan Gazit, PhD, DMD, co-director of the Skeletal Regeneration and Stem Cell Therapy Program in the Department of Surgery and the Cedars-Sinai Board of Governors Regenerative Medicine Institute. "We're combining an engineering approach with a biological approach to advance regenerative engineering, which we believe is the future of medicine."

Gazit was the principal investigator and co-senior author of the research study, published in the journal Science Translational Medicine.

More than 2 million bone grafts, frequently necessitated by severe injuries involving traffic accidents, war or tumor removal, are performed worldwide each year. Such injuries can create gaps between the edges of a fracture that are too large for the bone to bridge on its own. The grafts require implanting pieces from either the patient's or a donor's bone into the gap.

"Unfortunately, bone grafts carry disadvantages," said Gazit, a professor of surgery at Cedars-Sinai. "There are huge unmet needs in skeleton repair."

One problem is that enough healthy bone is not always available for repairs. Surgeries to remove a bone piece, typically from the pelvis, and implant it can lead to prolonged pain and expensive, lengthy hospitalizations. Further, grafts from donors may not integrate or grow properly, causing the repair to fail.

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The new technique developed by the Cedars-Sinai-led team could provide a much-needed alternative to bone grafts.

In their experiment, the investigators constructed a matrix of collagen, a protein the body uses to build bones, and implanted it in the gap between the two sides of a fractured leg bone in laboratory animals. This matrix recruited the fractured leg's own stem cells into the gap over a period of two weeks. To initiate the bone repair process, the team delivered a bone-inducing gene directly into the stem cells, using an ultrasound pulse and microbubbles that facilitated the entry of the gene into the cells.

Eight weeks after the surgery, the bone gap was closed and the leg fracture was healed in all the laboratory animals that received the treatment. Tests showed that the bone grown in the gap was as strong as that produced by surgical bone grafts, said Gadi Pelled, PhD, DMD, assistant professor of surgery at Cedars-Sinai and the study's co-senior author.

"This study is the first to demonstrate that ultrasound-mediated gene delivery to an animal's own stem cells can effectively be used to treat nonhealing bone fractures," Pelled said. "It addresses a major orthopedic unmet need and offers new possibilities for clinical translation."

The study involved six departments at Cedars-Sinai, plus investigators from Hebrew University in Jerusalem; the University of Rochester in Rochester, New York; and the University of California, Davis.

"Our project demonstrates how scientists from diverse disciplines can combine forces to find solutions to today's medical challenges and help develop treatments for the patients of tomorrow," said Bruce Gewertz, MD, surgeon-in-chief and chair of the Department of Surgery at Cedars-Sinai.

Explore further: Combining adult stem cells with hormone may speed bone fracture healing

More information: DOI: 10.1126/scitranslmed.aal3128 "In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs," Science Translational Medicine (2017). http://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aal3128

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Injured bones reconstructed by gene and stem cell therapies - Medical Xpress

Cancer therapy may work in unexpected way – Stanford Medical Center Report

Using antibodies to PD-1 or PD-L1 is one of the major advances in cancer immunotherapy, said Weissman, who is also the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. While most investigators accept the idea that anti-PD-1 and PD-L1 antibodies work by taking the brakes off of the T-cell attack on cancer cells, we have shown that there is a second mechanism that is also involved.

What Weissman and his colleagues discovered is that PD-1 activation also inhibits the anti-cancer activity of other immune cells called macrophages. Macrophages that infiltrate tumors are induced to create the PD-1 receptor on their surface, and when PD-1 or PD-L1 is blocked with antibodies, it prompts those macrophage cells to attack the cancer, Gordon said.

This mechanism is similar to that of another antibody studied in the Weissman lab: the antibody that blocks the protein CD47. Weissman and his colleagues showed that using anti-CD47 antibodies prompted macrophages to destroy cancer cells. The approach is now the subject of a small clinical trial in human patients.

As it stands, its unclear to what degree macrophages are responsible for the therapeutic success of the anti-PD-1 and anti-PD-L1 antibodies.

The practical implications of the discovery could be important, the researchers said. This could lead to novel therapies that are aimed at promoting either the T-cell component of the attack on cancer or promoting the macrophage component, Gordon said.

Another implication is that antibodies to PD-1 or PD-L1 may be more potent and broadly effective than previously thought. In order for T cells to attack cancer when you take the brakes off with antibodies, you need to start with a population of T cells that have learned to recognize specific cancer cells in the first place, Weissman said. Macrophage cells are part of the innate immune system, which means they should be able to recognize every kind of cancer in every patient.

Other Stanford co-authors of the study are associate professor of pathology Andrew Connolly, MD, PhD; visiting scholar Gregor Hutter, MD, PhD;instructor Rahul Sinha, PhD; postdoctoral scholars Roy Maute, PhD, Daniel Corey, MD, and Melissa McCracken, PhD; graduate students Benjamin Dulken, Benson George and Jonathan Tsai; and former graduate student Aaron Ring, MD, PhD.

The research was supported by the D.K. Ludwig Fund for Cancer Research, the A.P. Giannini Foundation, the Stanford Deans Fellowship, the National Institutes of Health (grant GM07365), the Swiss National Science Foundation and the National Center for Research Resources.

Weissman is a founder of the company Forty Seven Inc., which is sponsoring the clinical trial of the anti-CD47 antibody.

Stanfords departments of Pathology and of Developmental Biology also supported the work.

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Cancer therapy may work in unexpected way - Stanford Medical Center Report

Dr. Kenneth Pettine: Stem cell therapy is here to stay – Becker’s Orthopedic & Spine

At the forefront of regenerative medicine, Kenneth Pettine, MD, has participated in three FDA biologic studies. He works with Jeffery Donner, MD, at the Colorado Spine Institute . Dr. Pettine is the founder of the Orthopedic Stem Cell Institute, and is a pioneer in the field, with the only Stem Cell methods patent procedure in the nation.

"I'm convinced your body wants to heal itself," says Dr. Pettine. "The problem in orthopedics and spine is there's a paucity of blood supply to the joints or the disc in your back. If you injure your cartilage or disc, it has very little capacity to heal itself."

The key to regenerative medicine in orthopedics and spine lies in the mesenchymal stem cell, because it has the ability to differentiate into osteoblasts, chondroblasts or fibroblasts.

"This may be the most important stem cell in your body," Dr. Pettine explains. "The MSC is the cell that modulates your immune system through its paracrine ability to release numerous growth factors, cytokines, chemokines and inhibitorsIt's the conductor and your body is the orchestra."

The use of the MSC to treat orthopedic injuries is standard of care in veterinary medicine, with a good amount of Class 1 data proving safety and efficacy. Dr. Pettine believes humans could also potentially benefit from the use of the MSC to treat orthopedic and spine pathology.

Throughout his career, Dr. Pettine has served as principle investigator for 15 FDA IDE studies focused on non-fusion technology.

He helped with the ISTO Technologies FDA phase one study, which was the first biologic study ever conducted in the human spine in the United States. Using juvenile cartilage cells, the study saw significant reduction in patients' back pain and one-year results have been published.

Dr. Pettine also conducted an IRB study similar to the ISTO trial, utilizing autologous bone marrow concentrated cells to treat discogenic low back pain in 26 patients. This treatment has no FDA issues, as autologous bone marrow concentrated (BMC) cell therapy falls under "the practice of medicine" by the FDA under Section 361 of the Public Health Service Act's provisions.

The 30-minute procedure can be performed in an office or ambulatory surgery center with IV sedation or local anesthetic. Dr. Pettine has published one- and two-year results, and plans to publish three-year follow-up results soon.

The one-year results revealed the cell therapy "significantly reduces lumbar discogenic pain," according to Pettine et.al., Stem Cells 2015; 33:146-156. Out of the 26 patients, only six received surgery 36 months post-injection. Dr. Pettine reported a 72 percent average reduction in Oswestry Disability Index scores and 75 percent average decrease in Visual Analog Scales scores at 36 months.

"It seems to be long lasting," says Dr. Pettine. "We only re-injected two of the 26 patients at three-year follow up."

Of 210 patients with cervical degeneration Dr. Pettine has injected with BMC, about 70 percent reported a 65 percent improvement in pain at one year follow up. Any arthritic joint can be injected with BMC.

Although seeing positive results, Dr. Pettine notes this BMC cell therapy is not intended to replace surgery, but rather serve as a treatment for chronic conditions in patients who want an option prior to surgery. He believes this therapy will become more prevalent in the industry within three years to five years.

"I think it's important for surgeons to be more proactive with [stem cell therapy], because I promise this will not go away," cautions Dr. Pettine. "And if surgeons don't get involved in this, it will be taken over by non-surgeons."

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Dr. Kenneth Pettine: Stem cell therapy is here to stay - Becker's Orthopedic & Spine