Role of Stem Cells in Chronic Lung Diseases Revealed – Technology Networks

A novel population of lung stem cells plays an important role in regulating the pulmonary microvasculature the network of tiny blood vessels where oxygen and carbon dioxide exchange takes place.

The stem cells, called mesenchymal progenitor cells (MPCs), likely contribute to the pathobiology of chronic lung diseases, said Susan Majka, Ph.D., associate professor of Medicine.

Understanding the normal function and disease-associated dysfunction of MPCs could lead to earlier diagnosis and improved treatment for diseases such as pulmonary fibrosis, emphysema and pulmonary hypertension. The findings were reported this month in the Journal of Clinical Investigation.

Chronic lung diseases are marked by changes in lung tissue structure that include remodeling and loss of microvessels. The loss of microvessels impairs gas exchange, causing shortness of breath.

The vascular remodeling had been attributed to the endothelial cells that line blood vessels or the smooth muscle cells that surround them, Majka said. But endothelial and smooth muscle cells are terminally differentiated they are not likely to become other types of cells and Majka believed that unidentified stem cells, which can produce multiple types of mature cells with varied functions, were more likely to underlie tissue remodeling.

She and her colleagues had isolated vascular stem cells from mouse and human lungs and characterized them as MPCs that are located next to the microvasculature in the adult tissue. Now, they have used novel advanced lineage mapping tools to track the cells, under normal conditions and when signaling pathways associated with adult lung diseases are activated (Wnt signaling) or reduced (BMPR2 signaling).

When these cells are abnormal, animals develop vasculopathy a loss of structure in the microvessels and subsequently the lung. They lose the surfaces for gas exchange, Majka said.

The investigators also followed the cells after lung injury experimentally induced fibrosis (scarring). They discovered that the MPCs, which are abnormally activated after injury, formed an adaptive vascular structure that had never been previously characterized.

It appears to be a form of vascular mimicry, tubular structures that will circulate blood but are not normal blood vessels, Majka said. Its a new form of angiogenesis that could get blood into the middle of fibrotic areas, but our studies ended early after the injury, during peak fibrosis, and we dont know yet if its helping repair the injury or is actually detrimental.

Majka and her colleagues also used human lung tissues obtained from transplant or other surgeries to isolate MPCs. They compared human and mouse MPCs from normal and diseased lung tissue and showed that the cells have similar characteristics and gene expression profiles, defining the work as relevant to human disease.

Its very exciting to discover something new like this cell type that is so important in maintaining microvascular and lung tissue structure and that has potential implications in disease and repair, Majka said.

Understanding the MPCs, and other cell populations in the lung, is important for efforts to use stem cells to repair injured lung tissues, or to build lung tissue grafts.

Its critical to understand how different cells in the lung microenvironment regulate each other, and we really dont know that yet, Majka said.

By studying gene expression patterns in MPCs from normal and diseased or injured lungs, Majka and her colleagues have discovered new targets that may point to biomarkers for earlier detection of pulmonary diseases and that may guide the development of interventions that promote repair.

With pulmonary vascular diseases, by the time a patient has symptoms, theres already major damage to the microvasculature, Majka said. Using new biomarkers to detect the disease before symptoms arise would allow for earlier treatment, which could be effective at decreasing progression or even reversing the disease process.

In addition, MPCs are present in many adult tissues, including skin, kidney and uterus, suggesting that the findings may improve understanding of the microvascular basis of disease pathophysiology in these tissues.

This article has been republished frommaterialsprovided by Vanderbilt University Medical Center. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference:

Gaskill, C. F., Carrier, E. J., Kropski, J. A., Bloodworth, N. C., Menon, S., Foronjy, R. F., . . . Majka, S. M. (2017). Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction. Journal of Clinical Investigation. doi:10.1172/jci88629

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Role of Stem Cells in Chronic Lung Diseases Revealed - Technology Networks

California’s stem cell agency confronts uncertain future – Capitol Weekly

News

by DAVID JENSEN posted 05.23.2017

C. Randal Mills, the 45-year-old CEO of Californias $3 billion stem cell research program, is a man who loves his milestones.

A private pilot, he charts his course in the air from one specific point to the next. Three years ago, Mills brought that same sort of navigation to the state stem cell agency. Miss one of the agencys milestones, and if youre a stem cell scientist you may not crash and burn, but you could lose millions of dollars in research funding from the state.

Since the agencys inception, it has spent money at the rate of $22,000 an hour. But it has yet to finance a stem cell therapy that is available to the general public.

Mills has left an indelible stamp on the agency with his emphasis on concrete, measurable results. But he is resigning from the research program at the end of June in the midst of what some say is its last stage. His surprise departure to head the worlds largest bone marrow donor organization shocked many in Californias stem cell community. And it added to the unease about its future along with the future of possible stem cell therapies.

The California Institute for Regenerative Medicine (CIRM), as the agency is formally known, expects to run out of cash for new awards in just three years, which is a blink of an eye in biotech research. Since the agencys inception, it has spent money at the rate of $22,000 an hour. But it has yet to finance a stem cell therapy that is available to the general public. Nonetheless, there is talk of a new, $5 billion stem cell bond measure on the November 2018 ballot.

CIRM was created by California voters in 2004 when they approved a 10,000-word ballot initiative, Proposition 71. Voters also provided the agency with $3 billion in borrowed money (state bonds) that flows directly to the agency, untouched by the governor or the Legislature. The bond financing roughly doubles the cost of the research because of the interest expense.

Passage of the California initiative triggered a fresh wave of optimism and headlines that spoke of a new California gold rush this time in biotech.

The $34 million ballot campaign 13 years ago generated expectations that miraculous stem cell therapies were right around the corner. More than 40 Nobel Prize-winning scientists and actors such as Michael J. Fox campaigned for it. Christopher Reeve, who portrayed Superman but was later paralyzed in an accident, was featured in a TV ad that appeared after his death.

Stand up for those who cant, said Reeve from his wheelchair, calling on voters to support Proposition 71.

The agency came into being at a low point for the field of stem cell research. President George W. Bush had restricted federal funding for research using human embryonic stem cells. Researchers were disheartened. Younger scientists shied away from the field because of the funding uncertainties.

Passage of the California initiative triggered a fresh wave of optimism and headlines that spoke of a new California gold rush this time in biotech. While the gold rush is yet to be seen, the agency can point to a number of markers that it says show the program was worth the effort.

What particularly excites Mills and patient advocates are the dramatic and emotional stories of the handful of patients who have benefited from CIRM-connected clinical trials.

Independent, authoritative voices assessing the performance of the agency are almost non-existent. The Legislature has no oversight of the enterprise nor does the governor

Evangelina Padilla Vaccaro is one. Evangelina is alive today as the result of work at UCLA that has saved the lives of more than 30 persons afflicted with a fatal, rare immune disorder. She is perhaps the only four-year-old ever to address the governing board of the stem cell agency.

Thank you, she whispered to the board at a meeting last December. Evangelinas mother said more, her voice cracking, Thank you for keeping my family complete.

CIRM has pumped $52 million into the immune disorder research, which had been already underway for decades. However, only a handful of people can participate in the CIRM-connected clinical trials, such as Evangelinas, because of their experimental nature. Both the federal Food and Drug Administration, which ultimately controls the trials, and researchers move slowly to bring risky therapies to the general public.

The December meeting highlighted the personal success stories that can be found in the work financed by the agency. But four months later the prestigious scientific journal Nature carried a gloomier take. It published a piece on CIRM with a headline that described the agency as being in its last stage and facing its final test.

CIRM has made California a world leader in stem cell research, attracting some of the most talented scientists to the state to develop new treatments and funding world-class research facilities CIRM

The agency, however, is not yet ready for hospice care. Recently asked to cite the five most important things that Californians should know about the agency and its future, Kevin McCormack, senior director for communications, responded with much more. (The complete text of his statement can be found here.) His short list:

1) Research we have supported has cured more than 30 children of a fatal rare immune disorder. That same approach has also cured a young man of another rare immune disorder and is now being used to help find a cure for sickle cell anemia a condition that affects more than 100,000 people in the US, most of them African Americans.

2) We have funded 29 projects in clinical trials for a variety of diseases including heart disease, cancer, diabetes, HIV/AIDS, spinal cord injuries and the leading cause of vision loss and blindness in the US.

3) We are focused on adding another 40 new clinical trials by 2020, including rare diseases and those affecting children.

4) We place patients at the heart of everything we do and every decision we make. Nothing gets done at CIRM, including what we fund and how clinical trials are designed, without the input of patients and patient advocates. They know best what needs to be done and their voices are essential in making decisions about treatments that could change their lives, even save their lives.

5) CIRM has made California a world leader in stem cell research, attracting some of the most talented scientists to the state to develop new treatments and funding world-class research facilities in which the research is conducted free from federal restrictions.

Independent, authoritative voices assessing the performance of the agency are almost non-existent. The legislature has no oversight of the enterprise nor does the governor, a condition permitted legally by the ballot initiative. The initiative did create a body called the Citizens Financial Accountability and Oversight Committee, which meets once a year to consider the agencys finances. In recent years, it has been less than aggressive.

Jim Lott is a member of that group, which is chaired by the state controller. Over the years, however, Lott has expressed dissatisfaction with some aspects of the agency. Lott, who was executive vice president for decades of the Hospital Association of Southern California, said in an interview that the agency has done a really good job in seeding programs.

But he also described the ballot initiative as a very expensive tease. Lott said, They teased the public. They teased us with with Proposition 71. And they did not deliver on the tease, and I dont want them to be able to get away with that again.

According to calculations by theCalifornia Stem Cell Report, about 90 percent of the agencysawards have gone to institutionsthat are or have been represented onthe governing board.

If CIRM is to continue, he said it should be wrapped into the regular structure of state government and funded on a normal, annual budget basis. He also said the governing board should become advisory instead of currently making decisions on each application for state money.

We need to do this in a more responsible and accountable way, Lott said.

The most comprehensive review of the agency came in 2012 when the Institute of Medicine (IOM) reported the findings of its 17-month study of the agency. The IOM is a highly regarded national organization that provides studies on science, health and medical issues. The stem cell agency governing board commissioned the study at a cost of $700,000.

(The IOM has been renamed the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine.)

Harold Shapiro, former president of Princeton University and chairman of the IOM study, said in 2012 that the agency has done a remarkably good job overall in giving the state a prominent position in regenerative medicine. But he said the stem field has changed and the agency needed to change with it.

Currently, the top 10 recipients of CIRM largesse all have ties to its governing board.

When Shapiro appeared before the board to present the findings, some CIRM directors bridled at the studys far-reaching recommendations, many of which dealt with the built-in conflicts of interest on the board. The IOM proposals would have removed all board members from the grant review process and limited them to voting on a slate of applications rather than individual applications. More disclosure of personal conflicts of interest, including health matters, was also recommended.

Far too many board members represent organizations that receive CIRM funding or benefit from that funding. These competing personal and professional interests compromise the perceived independence of the ICOC (the CIRM governing board), introduce potential bias into the boards decision making and threaten to undermine confidence in the board, the IOM report said.

According to calculations by the California Stem Cell Report, about 90 percent of the agencys awards have gone to institutions that are or have been represented on the governing board.

Currently, the top 10 recipients of CIRM largesse all have ties to its governing board. The institutions are Stanford University, $320 million; UCLA, $275 million; UC San Diego, $177 million; UC San Francisco, $143 million; UC Davis, $129 million; USC, $110 million; UC Irvine, $106 million; City of Hope, $72 million; Cedars-Sinai Medical Center, $62 million, and Gladstone Institutes, $61 million.

We changed the way our board votes to ensure there would be no more concerns about the perception of conflict of interest. CIRM

The ballot initiative gave virtually all the institutions that were significant players in stem cell research a seat at the board table. The 29 board members cannot vote on applications from institutions that they are tied to. But they do set the rules, standards and scope of the grant programs.

In response to the IOM, the board approved what were termed dramatic changes in voting and other procedures to ease the perception of conflicts of interest. Shapiro called the changes significant.

The agency said last week,We changed the way our board votes to ensure there would be no more concerns about the perception of conflict of interest. By preventing heads of institutions who could receive stem cell funds from voting on any funding issue, we took that off the table so that we can focus on our main goal, helping patients.

The conflict case that has attracted the most public attention, however, did not involve directors, but Alan Trounson, Mills predecessor as president of agency. Seven days after Trounson left his CIRM post in 2014, he was appointed to the board of StemCells, Inc., a Newark, Calif. firm that was awarded more than $40 million in funding while Trounson was president of the agency. Trounson ultimately received $435,000 in total compensation for his duties on the StemCells, Inc., board. Trounson has denied any wrongdoing.

The Fair Political Practices Commission initiated an investigation and said in a 2015 letter to Trounson there was insufficient evidence to demonstrate a legal violation.

The loss of Mills has triggered concerns among some scientists that more CIRM employees will begin to look for work elsewhere. Mills has identified the risk of losing employees in his strategic plan. He has talked about finding ways to keep people on board, but nothing has been publicly disclosed.

On May 2, when Mills announced his coming departure to lead the National Marrow Donor Program in Minneapolis, the agency coupled the news with designation of an interim president, Maria Millan. She is currently the CIRM vice president for therapeutics. The agencys directors will discuss finding a permanent replacement at a closed-door meeting in July.

Mills said in an interview that Millan, a physician who has been with the agency since 2012, is the obvious choice to succeed him. Prior to joining CIRM, she served as a vice president and acting chief medical officer of StemCells, Inc., and was director of the pediatric organ transplant program at Stanford.

CIRMs general counsel, James Harrison is also leaving at the end of June. His announcement came in March, prior to Mills resignation. Harrison is a partner in the Oakland law firm of Remcho, Johansen & Purcell and wrote part of the stem cell initiative. Harrison worked under a contract between his firm and CIRM. He has been associated with the agency since its inception and has been a key leader with influence well beyond narrow legal issues.

Today CIRM is downto its last $650 million, having committed $2.2 billion for awards with the remainder going for operational expenses. The $650 million sounds ample, but when clinical trials are receiving $20 million in a single award, the money can go fast.

Coming to the financial rescue of CIRM may be Robert Klein, the Palo Alto multimillionaire real estate investment banker who led the 2004 campaign and became the agencys first chairman. He says he is ready to back a $5 billion bond issue for California voter approval in November of 2018. Americans for Cures, his nonprofit group, which shares space in Kleins Palo Alto headquarters, plans to poll California voters this fall, with the expectation that 70 percent of them will back the agency.

Klein did not respond to emailed questions for this article. But he made an appearance earlier this year at a CIRM-related event at the City of Hope in Duarte, Ca. Klein declared that a medical revolution is underway. And he said that the state of California now has the opportunity and privilege to lift the human condition if it will continue support of its 12-year-old stem cell research effort. Eds Note: David Jensen has published more than 4,000 items since 2005 dealing with California stem cell matters on his blog, the California Stem Cell Report. He formerly worked for The Sacramento Bee, UPI and spent 1975-6 working as a press aide for Gov. Jerry Brown in his first term in office.

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California's stem cell agency confronts uncertain future - Capitol Weekly

Study identifies RNA molecule that shields breast cancer stem cells … – Princeton University

Researchers from Princeton Universitys Department of Molecular Biology have identified a small RNA molecule that helps maintain the activity of stem cells in both healthy and cancerous breast tissue. The study, which will be published in the June issue of Nature Cell Biology, suggests that this "microRNA" promotes particularly deadly forms of breast cancer and that inhibiting the effects of this molecule could improve the efficacy of existing breast cancer therapies.

Stem cells give rise to the different cell types in adult tissues but, in order to maintain these tissues throughout adulthood, stem cells must retain their activity for decades. They do this by "self-renewing" dividing to form additional stem cells and resisting the effects of environmental signals that would otherwise cause them to prematurely differentiate into other cell types.

Many tumors also contain so-called "cancer stem cells" that can drive tumor formation. Some tumors, such as triple-negative breast cancers, are particularly deadly because they contain large numbers of cancer stem cells that self-renew and resist differentiation.

To identify factors that help non-cancerous mammary gland stem cells (MaSCs) resist differentiation and retain their capacity to self-renew, Yibin Kang, the Warner-Lambert/Parke-Davis Professor of Molecular Biology, and colleagues searched for short RNA molecules called microRNAs that can bind and inhibit protein-coding messenger RNAs to reduce the levels of specific proteins. The researchers identified one microRNA, called miR-199a, that helps MaSCs retain their stem-cell activity by suppressing the production of a protein called LCOR, which binds DNA to regulate gene expression. The team showed that when they boosted miR-199a levels in mouse MaSCs, they suppressed LCOR and increased normal stem cell function. Conversely, when they increased LCOR levels, they could curtail mammary gland stem cell activity.

Kang and colleagues found that miR-199a was also expressed in human and mouse breast cancer stem cells. Just as boosting miR-199a levels helped normal mammary gland stem cells retain their activity, the researchers showed that miR-199a enhanced the ability of cancer stem cells to form tumors. By increasing LCOR levels, in contrast, they could reduce the tumor-forming capacity of the cancer stem cells. In collaboration with researchers led by Zhi-Ming Shao, a professor at Fudan University Shanghai Cancer Center in China, Kang's team found that breast cancer patients whose tumors expressed large amounts of miR-199a showed poor survival rates, whereas tumors with high levels of LCOR had a better prognosis.

Kang and colleagues found that LCOR sensitizes cells to the effects of interferon-signaling molecules released from epithelial and immune cells, particularly macrophages, in the mammary gland. During normal mammary gland development, these cells secrete interferon-alpha to promote cell differentiation and inhibit cell division, the researchers discovered. By suppressing LCOR, miR-199a protects MaSCs from interferon signaling, allowing MaSCs to remain undifferentiated and capable of self-renewal.

The microRNA plays a similar role during tumorigenesis, protecting breast cancer stem cells from the effects of interferons secreted by immune cells present in the tumor. "This is a very nice study linking a normal and malignant mammary gland stem cell program to protection from immune modulators," said Michael Clarke, the Karel H. and Avice N. Beekhuis Professor in Cancer Biology at Stanford School of Medicine, Institute of Stem Cell Biology and Regenerative Medicine, who first discovered breast cancer stem cells but was not involved in this study. "It clearly has therapeutic implications for designing strategies to rationally target the breast cancer stem cells with immune modulators."

Toni Celi-Terrassa, an associate research scholar in the Kang lab and the first author of the study, said, "This study unveils a new property of breast cancer stem cells that give them advantages in their interactions with the immune system, and therefore it represents an excellent opportunity to exploit for improving immunotherapy of cancer."

"Interferons have been widely used for the treatment of multiple cancer types, Kang said. "These treatments might become more effective if the interferon-resistant cancer stem cells can be rendered sensitive by targeting the miR-199a-LCOR pathway."

Other authors on the paper were Daniel Liu, Abrar Choudhury, Xiang Hang, Yong Wei, Raymundo Alfaro-Aco, Rumela Chakrabarti, Christina DeCoste, Bong Ihn Koh and Heath Smith of the Department of Molecular Biology at Princeton University; Jose Zamalloa of the Department of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics at Princeton University; and Yi-Zhou Jiang, Jun-Jing Li and Zhi-Ming Shao of the Department of Breast Surgery at Fudan University Shanghai Cancer Center and the Department of Oncology at Shanghai Medical College, Fudan University.

This work was supported by a Susan G. Komen Fellowship to Toni Celi-Terrassa (PDF15332075) and grants from the Brewster Foundation, the Breast Cancer Research Foundation, the U.S. Department of Defense (BC123187) and the National Institutes of Health (R01CA141062) to Kang's laboratory.

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Study identifies RNA molecule that shields breast cancer stem cells ... - Princeton University

Stem-cell transplants show limited benefit for double-hit lymphoma patients in remission – Science Daily

Patients with double hit lymphoma (DHL) who undergo autologous stem-cell transplantation (autoSCT) after achieving remission are not more likely to remain in remission or live longer than patients who do not undergo autoSCT, according to a new analysis from the Perelman School of Medicine and the Abramson Cancer Center of the University of Pennsylvania. The study looked at long term outcomes for patients who achieved remission and, in most cases, found no clear benefit to the transplant, except potentially in patients who received standard front-line chemotherapy, who were less likely to remain in remission than those patients receiving intensive front-line chemotherapy. The findings are published this month in the Journal of Clinical Oncology.

DHL is a form of aggressive B cell non-Hodgkin lymphoma characterized by genetic alterations that drive the lymphoma's growth. This variant is associated with a poor prognosis as compared to other forms of aggressive B cell lymphomas, as patients with this disease survive only an average of two years after diagnosis. Relapses of this disease are almost always fatal, meaning that keeping patients in remission is crucial.

"A major dilemma for oncologists who treat this disease was whether or not to recommend the potentially harmful therapy of autoSCT to patients with this disease a strategy to help keep them in remission," said Daniel J. Landsburg, MD, an assistant professor of Hematology Oncology at Penn and the study's lead author.

Landsburg and his team looked at data on 159 patients from 19 different academic medical centers across the United States. Patients were diagnosed between 2006 and 2015, and all achieved remission following intensive front-line chemotherapy or the standard chemotherapy regimen containing rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Of the total patients, 62 underwent an autoSCT, while 97 did not. Landsburg noted that there were no significant differences between the patient groups at baseline.

"Our result is not explained by differences in patients' overall health or disease features," Landsburg said. "The transplant and non-transplant arms of this study were very well-matched."

Overall, 80 percent of the patients were still in remission three years later, and 87 percent were still alive. When researchers broke the patients into two groups, autoSCT and no autoSCT, they found 89 percent of autoSCT patients were still in remission at three years, as were 75 percent of patients who did not receive an autoSCT. Also at three years, 91 percent of autoSCT patients were still alive, compared to 85 percent of non-autoSCT patients. None of these differences were found to be statistically significant.

"Once these patients achieve remission, the data show they are likely to stay in remission," Landsburg said. "In the absence of a large randomized controlled trial, which would be very challenging to carry out in this case, this is the best evidence we have, and it shows there's no clear benefit to these patients undergoing autoSCT."

Landsburg did point to one exception in the data, and that was in patients who underwent RCHOP, the standard front-line chemotherapy regimen. Just 56 percent of them were still in remission at three years, far lower than patients who received the more intensive front-line therapies.

"Even if patients do go into remission with RCHOP, it appears to be less durable, so in these cases, going forward with autoSCT may still make sense," Landsburg said.

Landsburg says the next step will be to study features of patients who don't go into remission in order to understand why their disease is resistant to therapy and if that can be overcome with different treatment strategies. He says it's also important to try to find more effective therapies for DHL patients who relapse.

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Stem-cell transplants show limited benefit for double-hit lymphoma patients in remission - Science Daily

Cancer therapy may work in unexpected way, study finds – Science Daily

Antibodies to the proteins PD-1 and PD-L1 have been shown to fight cancer by unleashing the body's T cells, a type of immune cell. Now, researchers at the Stanford University School of Medicine have shown that the therapy also fights cancer in a completely different way, by prompting immune cells called macrophages to engulf and devour cancer cells.

The finding may have important implications for improving and expanding the use of this cancer treatment, the researchers said.

A study describing the work, which was done in mice, published online May 17 in Nature. The senior author is Irving Weissman, MD, professor of pathology and of developmental biology. The lead author is graduate student Sydney Gordon.

PD-1 is a cell receptor that plays an important role in protecting the body from an overactive immune system. T cells, which are immune cells that learn to detect and destroy damaged or diseased cells, can at times mistakenly attack healthy cells, producing autoimmune disorders like lupus or multiple sclerosis. PD-1 is what's called an "immune checkpoint," a protein receptor that tamps down highly active T cells so that they are less likely to attack healthy tissue.

How cancer hijacks PD-1

About 10 years ago, researchers discovered that cancer cells learn to use this immune safeguard for their own purposes. Tumor cells crank up the production of PD-L1 proteins, which are detected by the PD-1 receptor, inhibiting T cells from attacking the tumors. In effect, the proteins are a "don't kill me" signal to the immune system, the Stanford researchers said. Cancer patients are now being treated with antibodies that block the PD-1 receptor or latch onto its binding partner, PD-L1, to turn off this "don't kill me" signal and enable the T cells' attack.

"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.

Similar to anti-CD47 antibody

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 small clinical trials in human patients.

As it stands, it's 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."

Story Source:

Materials provided by Stanford University Medical Center. Original written by Christopher Vaughan. Note: Content may be edited for style and length.

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Cancer therapy may work in unexpected way, study finds - Science Daily

Cancer Immunotherapy May Work in Unexpected Way – Laboratory Equipment

Antibodies to the proteins PD-1 and PD-L1 have been shown to fight cancer by unleashing the body's T cells, a type of immune cell. Now, researchers at the Stanford University School of Medicine have shown that the therapy also fights cancer in a completely different way, by prompting immune cells called macrophages to engulf and devour cancer cells.

The finding may have important implications for improving and expanding the use of this cancer treatment, the researchers said.

A study describing the work, which was done in mice, was published online May 17 in Nature. The senior author is Irving Weissman, MD, professor of pathology and of developmental biology. The lead author is graduate student Sydney Gordon.

PD-1 is a cell receptor that plays an important role in protecting the body from an overactive immune system. T cells, which are immune cells that learn to detect and destroy damaged or diseased cells, can at times mistakenly attack healthy cells, producing autoimmune disorders like lupus or multiple sclerosis. PD-1 is what's called an "immune checkpoint," a protein receptor that tamps down highly active T cells so that they are less likely to attack healthy tissue.

How cancer hijacks PD-1

About 10 years ago, researchers discovered that cancer cells learn to use this immune safeguard for their own purposes. Tumor cells crank up the production of PD-L1 proteins, which are detected by the PD-1 receptor, inhibiting T cells from attacking the tumors. In effect, the proteins are a "don't kill me" signal to the immune system, the Stanford researchers said. Cancer patients are now being treated with antibodies that block the PD-1 receptor or latch onto its binding partner, PD-L1, to turn off this "don't kill me" signal and enable the T cells' attack.

"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.

Similar to anti-CD47 antibody

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, it's 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."

Continued here:
Cancer Immunotherapy May Work in Unexpected Way - Laboratory Equipment

Basis of ‘leaky’ brain blood vessels in Huntington’s disease identified – UCI News

Irvine, Calif., May 16, 2017 By using induced pluripotent stem cells to create endothelial cells that line blood vessels in the brain for the first time for a neurodegenerative disease, University of California, Irvine neurobiologists and colleagues have learned why Huntingtons disease patients have defects in the blood-brain barrier that contribute to the symptoms of this fatal disorder.

Now we know there are internal problems with blood vessels in the brain, said study leader Leslie Thompson, UCI professor of psychiatry & human behavior and neurobiology & behavior. This discovery can be used for possible future treatments to seal the leaky blood vessels themselves and to evaluate drug delivery to patients with HD.

The blood-brain barrier protects the brain from harmful molecules and proteins. It has been established that in Huntingtons and other neurodegenerative diseases there are defects in this barrier adding to HD symptoms. What was not known was whether these defects come from the cells that constitute the barrier or are secondary effects from other brain cells.

To answer that, Thompson and colleagues from UCI, Columbia University, the Massachusetts Institute of Technology and Cedars-Sinai Medical Center reprogrammed cells from HD patients into induced pluripotent stem cells, then differentiated them into brain microvascular endothelial cells those that form the internal lining of blood vessels and prevent leakage of blood proteins and immune cells.

The researchers discovered that blood vessels in the brains of HD patients become abnormal due to the presence of the mutated Huntingtin protein, the hallmark molecule linked to the disease. As a result, these blood vessels have a diminished capacity to form new blood vessels and are leaky compared to those derived from control patients.

The chronic production of the mutant Huntingtin protein in the blood vessel cells causes other genes within the cells to be abnormally expressed, which in turn disrupts their normal functions, such as creating new vessels, maintaining an appropriate barrier to outside molecules, and eliminating harmful substances that may enter the brain.

In addition, by conducting in-depth analyses of the altered gene expression patterns in these cells, the study team identified a key signaling pathway known as the Wnt that helps explain why these defects occur. In the healthy brain, this pathway plays an important role in forming and preserving the blood-brain barrier. The researchers showed that most of the defects in HD patients blood vessels can be prevented when the vessels are exposed to a compound (XAV939) that inhibits the activity of the Wnt pathway.

This is the first induced pluripotent stem cell-based model of the blood-brain barrier for a neurodegenerative disease. The study appears in the journal Cell Reports, with a parallel study from Cedars-Sinai Medical Center in Cell Stem Cell that advances the first model for a neurodevelopmental disease that specifically affects the blood-brain barrier.

These studies together demonstrate the incredible power of iPSCs to help us more fully understand human disease and identify the underlying causes of cellular processes that are altered, said Ryan Lim, a postgraduate research scientist at the Institute for Memory Impairments and Neurological Disorders, or UCI MIND, who initiated the UCI work.

We show a proof-of-concept therapy where we could reverse some of the abnormalities in the blood vessel cells by treating them with a drug, added Thompson, who is affiliated with both UCI MIND and the Sue & Bill Gross Stem Cell Research Center.

The future direction of this study is to develop ways to test how drugs may be delivered to the brain of HD patients and to examine additional treatment strategies using our understanding of the underlying causes of abnormalities in brain blood vessels, said study co-leader Dritan Agalliu, assistant professor of pathology & cell biology at Columbia University Medical Center.

Chris Quan, Andrea M. Reyes-Ortiz, Jie Wu, Jennifer Stocksdale and Malcolm S. Casale of UCI; Amanda J. Kedaigle, Theresa A. Gipson, Ernest Fraenkel and David E. Housman of MIT; Gad D. Vatine and Clive N. Svendsen of Cedars-Sinai; and Sarah E. Lutz of Columbia University also contributed to the study, which was supported in part by the American Heart Association, California Institute for Regenerative Medicine and National Institutes of Health.

About the University of California, Irvine: Founded in 1965, UCI is the youngest member of the prestigious Association of American Universities. The campus has produced three Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 30,000 students and offers 192 degree programs. Its located in one of the worlds safest and most economically vibrant communities and is Orange Countys second-largest employer, contributing $5 billion annually to the local economy. For more on UCI, visit http://www.uci.edu.

Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UCI faculty and experts, subject to availability and university approval. For more UCI news, visit news.uci.edu. Additional resources for journalists may be found at communications.uci.edu/for-journalists.

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Basis of 'leaky' brain blood vessels in Huntington's disease identified - UCI News

Press Release: New Stem Cell Collection Center Opens in Boston – The Scientist

Press Release: New Stem Cell Collection Center Opens in Boston The Scientist StemExpress expands to the East Coast with the launch of a new Stem Cell Collection Center to meet the growing demand of its products. This new donation center, located in Arlington Massachusetts, will expand the company's ability to collect and ...

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Press Release: New Stem Cell Collection Center Opens in Boston - The Scientist

Basis of ‘leaky’ brain blood vessels in Huntington’s Disease identified – Science Daily

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Basis of 'leaky' brain blood vessels in Huntington's Disease identified Science Daily To answer that, Thompson and colleagues from UCI, Columbia University, the Massachusetts Institute of Technology and Cedars-Sinai Medical Center reprogrammed cells from HD patients into induced pluripotent stem cells, then differentiated them into ... Team creates self-renewing hematopoietic stem cells for transplantationMedical Xpress Approaching a decades-old goal: Making blood stem cells from patients' own cellsEurekAlert (press release) all 21 news articles »

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Basis of 'leaky' brain blood vessels in Huntington's Disease identified - Science Daily

Stem cell transplants may advance ALS treatment by repair of blood-spinal cord barrier – Medical Xpress

May 15, 2017 An MRI with increased signal in the posterior part of the internal capsule which can be tracked to the motor cortex consistent with the diagnosis of ALS. Credit: Frank Gaillard/Wikipedia

Researchers at the University of South Florida show in a new study that bone marrow stem cell transplants helped improve motor functions and nervous system conditions in mice with the disease Amyotrophic Lateral Sclerosis (ALS) by repairing damage to the blood-spinal cord barrier.

In a study recently published in the journal Scientific Reports, researchers in USF's Center of Excellence for Aging and Brain Repair say the results of their experiment are an early step in pursuing stem cells for potential repair of the blood-spinal cord barrier, which has been identified as key in the development of ALS. USF Health Professor Svitlana Garbuzova-Davis, PhD, led the project.

Previous studies in development of various therapeutic approaches for ALS typically used pre-symptomatic mice.

"This is the first study advancing barrier repair that treats symptomatic mice, which more closely mirrors conditions for human patients," Dr. Garbuzova-Davis said.

Using stem cells harvested from human bone marrow, researchers transplanted cells into mice modeling ALS and already showing disease symptoms. The transplanted stem cells differentiated and attached to vascular walls of many capillaries, beginning the process of blood-spinal cord barrier repair.

The stem cell treatment delayed the progression of the disease and led to improved motor function in the mice, as well as increased motor neuron cell survival, the study reported.

ALS is a progressive neurodegenerative disease that affects neuronal cells in the brain and the spinal cord, which send signals to control muscles throughout the body. The progressive degeneration of motor neuron cells leads to death from ALS. More than 6,000 Americans each year are diagnosed with the disease.

Because stem cells have the ability to develop into many different cell types in the body, researchers at USF's Center of Excellence for Aging and Brain Repair, Department of Neurosurgery & Brain Repair have focused on using stem cells to restore function lost through neurodegenerative disorders or injuries.

Damage to the barrier between the blood circulatory system and the central nervous system has been recently recognized as a factor in ALS development, leading researchers to work on targeting the barrier for repair as a potential strategy for ALS therapy.

In this study, the ALS mice were given intravenous treatments of one of three different doses of the bone marrow stem cells. Four weeks after treatment, the scientists determined improved motor function and enhanced motor neuron survival. The mice receiving the higher doses of stem cells fared better in the study, the researcher noted.

The transplanted stem cells had differentiated into endothelial cells - which form the inner lining of a blood vessel, providing a barrier between blood and spinal cord tissueand attached to capillaries in the spinal cord. Furthermore, the researchers observed reductions in activated glial cells, which contribute to inflammatory processes in ALS.

Explore further: Discovery offers new hope to repair spinal cord injuries

More information: Svitlana Garbuzova-Davis et al, Endothelial and Astrocytic Support by Human Bone Marrow Stem Cell Grafts into Symptomatic ALS Mice towards Blood-Spinal Cord Barrier Repair, Scientific Reports (2017). DOI: 10.1038/s41598-017-00993-0

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Stem cell transplants may advance ALS treatment by repair of blood-spinal cord barrier - Medical Xpress