Therapeutic benefits of synthetic cardiac stem cells

Researchers from North Carolina State University, the University of North Carolina at Chapel Hill and First Affiliated Hospital of Zhengzhou University have developed a synthetic version of a cardiac stem cell. These synthetic stem cells offer therapeutic benefits comparable to those from natural stem cells and could reduce some of the risks associated with stem cell therapies. Additionally, these cells have better preservation stability and the technology is generalizable to other types of stem cells.

Synthetic cardiac stem cells could offer therapeutic benefits without associated risks.
Credit: Alice Harvey, NC State University.

Stem cell therapies work by promoting endogenous repair; that is, they aid damaged tissue in repairing itself by secreting “paracrine factors,” including proteins and genetic materials. While stem cell therapies can be effective, they are also associated with some risks of both tumor growth and immune rejection. Also, the cells themselves are very fragile, requiring careful storage and a multi-step process of typing and characterization before they can be used.

Ke Cheng, associate professor of molecular biomedical sciences at NC State University, associate professor in the joint biomedical engineering program at NC State and UNC and adjunct associate professor at the UNC Eshelman School of Pharmacy, led a team in developing the synthetic version of a cardiac stem cell that could be used in off-the-shelf applications. Cheng and his colleagues fabricated a cell-mimicking microparticle (CMMP) from poly (lactic-co-glycolic acid) or PLGA, a biodegradable and biocompatible polymer. The researchers then harvested growth factor proteins from cultured human cardiac stem cells and added them to the PLGA. Finally, they coated the particle with cardiac stem cell membrane.

When tested in vitro, both the cell-mimicking microparticle and cardiac stem cell promoted the growth of cardiac muscle cells. They also tested the cell-mimicking microparticle in a mouse model with myocardial infarction, and found that its ability to bind to cardiac tissue and promote growth after a heart attack was comparable to that of cardiac stem cells. Due to its structure, cell-mimicking microparticle cannot replicate – reducing the risk of tumor formation.

“The synthetic cells operate much the same way a deactivated vaccine works,” Cheng says. “Their membranes allow them to bypass the immune response, bind to cardiac tissue, release the growth factors and generate repair, but they cannot amplify by themselves. So you get the benefits of stem cell therapy without risks.”

The synthetic stem cells are much more durable than human stem cells, and can tolerate harsh freezing and thawing. They also don’t have to be derived from the patient’s own cells. And the manufacturing process can be used with any type of stem cell.

“We are hoping that this may be a first step toward a truly off-the-shelf stem cell product that would enable people to receive beneficial stem cell therapies when they’re needed, without costly delays,” Cheng says.

Citation: Junnan Tang, Deliang Shen, Thomas George Caranasos, Zegen Wang, Tyler A. Allen, Adam Vandergriff, Michael Taylor Hensley, Phuong-Uyen Dinh, Jhon Cores, Taosheng Li, Jinying Zhang, Quancheng Kan, Ke Cheng. “Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome”. Nature Communications 2016.
DOI: 10.1038/NCOMMS13724
Research funding: National Institutes of Health, NC State Chancellor’s Innovation Fund, University of North Carolina General Assembly Research Opportunities Initiative.
Adapted from press release by North Carolina State University

Harmine, substance in ayahuasca brew promotes neural progenitor cell proliferation.

Ayahuasca is a beverage that has been used for centuries by Native South-Americans. Studies suggest that it exhibits anxiolytic and antidepressant effects in humans. One of the main substances present in the beverage is harmine, a beta-carboline which potential therapeutic effects for depression has been recently described in mice.

“It has been shown in rodents that antidepressant medication acts by inducing neurogenesis. So we decided to test if harmine, an alkaloid with the highest concentration in the psychotropic plant decoction ayahuasca, would trigger neurogenesis in human neural cells”, said Vanja Dakic, PhD student and one of the authors in the study.

In order to elucidate these effects, researchers from the D’Or Institute for Research and Education (IDOR) and the Institute of Biomedical Sciences at the Federal University of Rio de Janeiro (ICB-UFRJ) exposed human neural progenitors to this beta-carboline. After four days, harmine led to a 70% increase in proliferation of human neural progenitor cells.

Researchers were also able to identify how the human neural cells respond to harmine. The described effect involves the inhibition of DYRK1A, which is located on chromosome 21 and is over-activated in patients with Down syndrome and Alzheimer’s Disease.

“Our results demonstrate that harmine is able to generate new human neural cells, similarly to the effects of classical antidepressant drugs, which frequently are followed by diverse side effects. Moreover, the observation that harmine inhibits DYRK1A in neural cells allows us to speculate about future studies to test its potential therapeutic role over cognitive deficits observed in Down syndrome and neurodegenerative diseases”, suggests Stevens Rehen, researcher from IDOR and ICB-UFRJ.

Citation: “Harmine stimulates proliferation of human neural progenitors.” Vanja Dakic, Renata de Moraes Maciel, Hannah Drummond, Juliana M. Nascimento, Pablo Trindade & Stevens K. Rehen. PeerJ 2016 vol: 4 pp: e2727.
DOI: 10.7717/peerj.2727
Research funding: Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro, Conselho Nacional de Desenvolvimento Científico e Tecnológico
Adapted from press release by D’Or Institute for Research and Education.

Research shows meninges contain neural progenitor stem cells

In a cross-domain study directed by professor Peter Carmeliet, researchers discovered unexpected cells in the protective membranes that enclose the brain, the so-called meninges. These ‘neural progenitors’ – or stem cells that differentiate into different kinds of neurons – are produced during embryonic development. These findings show that the neural progenitors found in the meninges produce new neurons after birth – highlighting the importance of meningeal tissue as well as these cells’ potential in the development of new therapies for brain damage or neurodegeneration. A paper highlighting the results was published in the leading scientific journal Cell Stem Cell.

Before the discoveries of the last few decades, neurologists once thought that the brain became ‘static’ after childhood. This dogma has changed, with researchers finding more and more evidence that the brain is capable of healing and regenerating in adulthood, thanks to the presence of stem cells. However, neuronal stem cells were generally believed to only reside within the brain tissue, not in the membranes surrounding it.

Believed in the past to serve a mainly protective function to dampen mechanical shocks, the meninges have been historically underappreciated by science as having neurological importance in its own right. The data gathered by the team challenges the current idea that neural precursors – or stem cells that give rise to neurons – can only be found inside actual brain tissue.

Prof. Peter Carmeliet said “The neuronal stems cells that we discovered inside the meninges differentiate to full neurons, electrically-active and functionally integrated into the neuronal circuit. To show that the stem cells reside in the meninges, we used the extremely powerful single-cell RNA sequencing technique, a very novel top-notch technique, capable of identifying the (complex gene expression signature) nature of individual cells in a previously unsurpassed manner, a première at VIB.”

 When it comes to future leads for this discovery, the scientists also see possibilities for translation into clinical application, though future work is required. Prof. Peter Carmeliet said “An intriguing question is whether these neuronal stem cells in the meninges could lead to better therapies for brain damage or neurodegeneration. However, answering this question would require a better understanding of the molecular mechanisms that regulate the differentiation of these stem cells. How are these meningeal stem cells activated to become different kinds of neurons? Can we therapeutically ‘hijack’ their regeneration potential to restore dying neurons in, for example, Alzheimer’ Disease, Parkinson’s Disease, amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders? Also, can we isolate these neurogenic progenitors from the meninges at birth and use them for later transplantation? These findings open up very exciting research opportunities for the future.”

 Moving into unchartered territory is high risk, and can offer high gain, but securing funding for such type of research is challenging. However, Carmeliet’s discoveries were made possible to a large extent by funding through “Opening the Future: pioneering without boundaries”, a recently created Mecenas Funding Campaign for funding of high-risk brain research but with potential for breakthrough discoveries, started up by the KU Leuven in 2013 and unique in Flanders.

Citation: “Neurogenic Radial Glia-like Cells in Meninges Migrate and Differentiate into Functionally Integrated Neurons in the Neonatal Cortex”. Francesco Bifari1, Ilaria Decimo1, Annachiara Pino, Enric Llorens-Bobadilla, Sheng Zhao, Christian Lange, Gabriella Panuccio, Bram Boeckx, Bernard Thienpont, Stefan Vinckier, Sabine Wyns, Ann Bouché, Diether Lambrechts, Michele Giugliano, Mieke Dewerchin, Ana Martin-Villalba, Peter Carmeliet. Cell Stem Cell 2016.
DOI: http://dx.doi.org/10.1016/j.stem.2016.10.020
Research funding: Mecenas funding initiative by the KU Leuven
Adapted from press release by VIB Vlaams Instituut Voor Biotechnologie (The Flaunders institute of biotechnology)

Bone marrow derived stem cell therapy shown to reduce inflammation in traumatic brain injury

Results of a cellular therapy clinical trial for traumatic brain injury (TBI) using a patient’s own stem cells showed that the therapy appears to dampen the body’s neuroinflammatory response to trauma and preserve brain tissue, according to researchers at The University of Texas Health Science Center at Houston (UTHealth). The results, which also confirmed safety and feasibility as cited in earlier studies, were published online Nov. 1 in the journal STEM CELLS.

According to the Centers for Disease Control, 1.7 million Americans sustain a traumatic brain injury annually. Of those, 275,000 are hospitalized and 52,000 die. TBI is a contributing factor to a third of all injury-related deaths in the country. According to published research cited in the paper, more than 6.5 million patients are burdened by the physical, cognitive and psychosocial deficits associated with TBI, leading to an economic impact of approximately $60 billion.

There are few current therapies to treat TBI. Critical care teams work to stabilize patients and surgery is sometimes necessary to remove or repair damaged blood vessels or tissue, as well as provide relief from swelling.

To potentially open a new avenue of treatment, Cox has been researching cell therapy for neurological disease in pre-clinical and clinical trials for more than two decades. The new study builds on his previously published research showing that autologous stem cell therapy after TBI is safe and reduces the therapeutic intensity requirements of neurocritical care. The theory is that the stem cells work in the brain to alleviate the body’s inflammatory response to the trauma.

Researchers enrolled 25 patients in a dose-escalation format with five controls followed by five patients in each of three different doses followed by five more controls for a total of 25. Bone marrow harvesting, cell processing and re-infusion occurred within 48 hours after injury. Cellular processing was done at The Evelyn H. Griffin Stem Cell Therapeutics Research Laboratory at McGovern Medical School.

Functional and neurocognitive outcomes were measured and correlated with imaging data including magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) of white brain matter.

According to the authors, despite the treatment group having greater injury severity, there was structural preservation of critical regions of interest that correlated with functional outcomes and key inflammatory cytokines were down-regulated after bone marrow cell infusion.

Citation: Cox, Charles S., Robert A. Hetz, George P. Liao, Benjamin M. Aertker, Linda Ewing‐Cobbs, Jenifer Juranek, Sean I. Savitz et al. “Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells.” STEM CELLS.
DOI: 10.1002/stem.2538
Research funding:US Department of Defense, National Institutes of Health, Glassell Foundation Stem Cell Research Program, The Brown Foundation, Inc.
Adapted from press release by The University of Texas Health Science Center at Houston 

Researchers used stem cells to make new cartilage and repair damaged joints

Columbia College of Dental Medicine researchers have identified stem cells that can make new cartilage and repair damaged joints. The cells reside within the temporomandibular joint (TMJ), which articulates the jaw bone to the skull. When the stem cells were manipulated in animals with TMJ degeneration, the cells repaired cartilage in the joint. A single cell transplanted in a mouse spontaneously generated cartilage and bone and even began to form a bone marrow niche. The findings were published on October 10 in Nature Communications.

“This is very exciting for the field because patients who have problems with their jaws and TMJs are very limited in terms of clinical treatments available,” said Mildred C. Embree, DMD, PhD, assistant professor of dental medicine at Columbia University Medical Center (CUMC) and the lead author of the study. Dr. Embree’s team, the TMJ Biology and Regenerative Medicine Lab, conducted the research with colleagues including Jeremy Mao, DDS, PhD, the Edwin S. Robinson Professor of Dentistry (in Orthopedic Surgery) at CUMC.

Up to 10 million people in the United States, primarily women, have TMJ disorders, according to the National Institutes of Health. Options for treatment currently include either surgery or palliative care, which addresses symptoms but can’t regenerate the damaged tissue. Dr. Embree’s findings suggest that stem cells already present in the joint could be manipulated to repair it.

Cartilage helps to cushion the joints and allows them to move smoothly. The type of cartilage within the TMJ is fibrocartilage, which is also found in the knee meniscus and in the discs between the vertebrae. Because fibrocartilage cannot regrow or heal, injury or disease that damages this tissue can lead to permanent disability.

Medical researchers have been working to use stem cells, immature cells that can develop into various types of tissue, to regenerate cartilage. Given the challenges of transplanting donor stem cells, such as the possibility of rejection by the recipient, researchers are especially interested in finding ways to use stem cells already living in the body.

“The implications of these findings are broad,” said Dr. Mao, “including for clinical therapies. They suggest that molecular signals that govern stem cells may have therapeutic applications for cartilage and bone regeneration. Cartilage and certain bone defects are notoriously difficult to heal.” Dr. Mao is co-director of the Center for Craniofacial Regeneration at Columbia. His own research with stem cells has regenerated teeth and the meniscus, the pad of cartilage within the knee joint, and the TMJ in 2003.

In a series of experiments described in the new report, Dr. Embree, Dr. Mao, and their colleagues isolated fibrocartilage stem cells (FCSCs) from the joint and showed that the cells can form cartilage and bone, both in the laboratory and when implanted into animals. “I didn’t have to add any reagents to the cells,” Dr. Embree said. “They were programmed to do this.” And while some approaches to regenerating injured tissue require growth factors or biomaterials for the cells to grow on, she noted, the FCSCs grew and matured spontaneously.

Dr. Embree and her team also identified a molecular signal, Wnt, that depletes FCSCs and causes cartilage degeneration. Injecting a Wnt-blocking molecule called sclerostin into degenerated TMJs in animals stimulated cartilage growth and healing of the joint.

She and her colleagues are now searching for other small molecules that could be used to inhibit Wnt and promote FCSC growth. The idea, according to Dr. Embree, will be to find a drug with minimal side effects that could be injected right into the joint.

Children with juvenile idiopathic arthritis can have stunted jaw growth that can’t be treated with existing drugs, Dr. Embree noted. Since the TMJ is a growth center for the jaw, the new research may offer strategies for treating these children, and lead to a better understanding of how the jaw grows and develops. While orthodontists currently rely on clunky technologies like headgear to modify jaw growth, she added, the findings could point towards ways to modulate growth on the cellular level.

Ultimately, Dr. Embree and her team say, the findings could lead to strategies for repairing fibrocartilage in other joints, including the knees and vertebral discs. “Those types of cartilage have different cellular constituents, so we would have to really investigate the molecular underpinnings regarding how these cells are regulated,” the researcher said.

Publication: Exploiting endogenous fibrocartilage stem cells to regenerate cartilage and repair joint injury.  DOI: http://dx.doi.org/10.1038/NCOMMS13073
Adapted from press release by Columbia University Medical Center