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Stem cell breakthroughs in regenerative medicine and GvHD
PHILADELPHIA—Cell therapies are still a relatively novel approach to treatment, if only because much remains to be discovered about how they work, how they can be utilized and also, it seems, what stem cells are available for us to explore and manipulate. This was shown recently in a paper titled “Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor” in Nature that describes newly identified stem cells in the lung that multiply rapidly after a pulmonary injury.
This finding may offer an opportunity for innovative treatments that could be employed to harness the body’s ability to regenerate—particularly to treat lung diseases across the lifespan, from premature infants to the elderly.
In this work, scientists and clinicians at Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania (Penn) focused on mouse and then human alveoli, which are tiny compartments in the lung where gas exchange occurs, as oxygen is taken up by the blood and carbon dioxide is removed. Both in the human and animal models, the research team identified a new cell lineage that they are calling alveolar epithelial progenitor (AEP) cells.
“These cells sits quietly, but poised, in the lung until an injury activates them to proliferate and differentiate,” said co-first author Dr. David B. Frank, a pediatric cardiologist at CHOP. “If we can learn to manipulate the biological signals in this process, we may be able to regenerate lung tissue in patients.”
“One of the most important places to better understand lung regeneration is the alveoli,” added Dr. Edward E. Morrisey, director of the Penn Center for Pulmonary Biology and scientific director of Penn’s Institute for Regenerative Medicine, who led the research team. “To better understand these delicate structures, we have been mapping the different types of cells within the alveoli.”
Morrisey stresses that understanding cell-cell interactions is extremely important in discovering new biological players and molecular pathways that could lead to future therapies. In this case, with the AEP cells, the researchers found that this cell system is evolutionarily conserved across separated species—therefore, they share similar characteristics in both mice and humans. According to the team, the underlying genes code for a similar set of proteins and respond to a similar set of signals, which would allow researchers to investigate specific biological mechanisms in mice and have a reasonable clue as to how these cells function in humans. They were also able to perform experiments in organoid models—three-dimensional cell cultures that simulated specific ways that lungs function in living lower organisms.
In this study, the researchers studied how mice responded to lung injury caused by influenza virus. They discovered mechanisms by which alveolar cells are sensitive to Wnt signals, an important and powerful stem cell signaling pathway. Wnt signals, along with another set of signals called Fgf signals, act on the normally quiescent AEP cells in the lung to orchestrate their response to injury. Those AEP cells multiply rapidly and differentiate into alveolar cells, thereby regenerating lung tissue.
“As we have seen during this influenza season, lung damage from viruses and inflammation can be devastating,” said Frank. “However, we now understand how the alveolar epithelial niche regenerates following injury. With this information, we may able to design pathway-specific modifiers or cell-based therapies to treat lung damage.”
According to the researchers, the AEP findings could also lay the foundation for new treatments for children with bronchopulmonary dysplasia and adults with chronic obstructive pulmonary disease, among other possible conditions. Frank suggests the knowledge might even inform future tissue engineering treatments for premature babies or patients needing lung transplantation. Also, because respiration is a key component of the cardiovascular system, Frank expects to pursue future research into tissue regeneration in the vascular system—as a pediatric cardiologist, he has a special focus on children with pulmonary hypertension, often a complication of congenital heart disease.
Looking over to recent European research, a type of cell found in the placenta may help people suffering from painful and life-threatening severe acute graft-versus-host disease (GvHD). GvHD occurs in up to 70 percent of patients who have undergone a stem cell transplant to treat a disease such as leukemia, using cells other than their own, and develops because the donor’s immune cells attack the patient’s normal cells. This research, detailed in the paper “Placenta-derived decidua stromal cells for treatment of severe acute graft-versus-host disease” in STEM CELLS Translational Medicine, focused on decidua stromal cells (DSCs), following on to research more than a decade on from the same team into mesenchymal stromal cells (MSCs).
The genesis of this work goes back to dealing with the fact that while steroids are used to prevent or lessen the effects of GvHD, some patients don’t respond to them, meaning of course that new and better treatments are needed. So, more than 10 years ago, a team from the Karolinska Institute near Stockholm looked at MSCs as a possible solution. However, despite promising initial results, long-term overall survival of the patients tested was no better than those in the control group.
In this latest study, the same team of researchers, led by Dr. Olle Ringdén, DSCs might offer relief. These cells differ from the MSCs used in the earlier study as they are collected from the placenta rather than bone marrow.
“There were a couple of things that led us to be curious about this,” Ringdén said. “First, [the] placenta plays an important role in helping the mother’s body tolerate the developing fetus and, second, [the] placenta has been used in Africa for 100 years to successfully treat burn injuries. This speaks somewhat to its effectiveness and safety. We also found that placenta-derived DSCs are immunosuppressive in vitro and in vivo, which led us to wonder if they might cure severe acute GvHD.”
So, the team brought together 38 patients in danger of dying from GvHD—including 25 who who were not responding to steroid treatments—into a small clinical trial wherein one group of 17 patients received higher doses of the DSCs, but fewer overall treatments, than a second group of 21 patients. One year later, the second group had a 76-percent survival rate versus the first group’s 47-percent rate. Both DSC-treated groups did much better than a control group of patients receiving bone marrow-derived MSCs, whose survival rate was 20 percent. Even the patients who didn’t respond to steroids seemed to respond to the DSCs, with a one-year survival rate that was 31 percent for those in Group 1 and 73 percent in Group 2.
“Collectively, we think these data demonstrate that DSCs are a promising treatment for severe acute GvHD. But it was a small patient group, so to further assess safety and efficacy a larger prospective trial will be necessary,” Ringdén noted. “If an effective therapy for severe acute GvHD is indeed found and validated, it will increase the usefulness of stem cell transplantation with a possible broadening of indications.”