Research topic: Investigating whether culturing human mesenchymal stem cells (hMSCs) with parathyroid hormone can significantly increase their potential to proliferate prior to differentiation, target a fracture site, and sustain their pluripotent ability to differentiate into cells needed for fracture healing
Research results: Showed that parathyroid hormone does increase hMSCs’ ability to heal fractures
Patient care application of results: Intravenous-hMSC therapy that could aid in healing fractures with insufficient or non-unions
Simplified patient care application: Better, non-invasive treatment methods for patients, especially the elderly, with difficult-to-heal fractures
Turning Obstacles into Opportunities
OREF grant recipient investigates non-invasive ways to treat patients with difficult-to-heal fractures
In his career as a radiologist and clinician scientist, Chao Xie, MD, has often been just as inspired by limitations as by opportunities.
Three decades ago, medical technology was very limited in his home country of China. Dr. Xie experienced frustration personally as a first-year medical student, when his father received a late diagnosis of cancer because CT scans were not widely applied in China. The young student became determined to apply his passion for technology to help improve diagnostic options.
“I thought earlier diagnosis was a top priority, so I chose a career in radiology,” Dr. Xie explained.
But only being able to diagnose—and not treat—illness was also a source of frustration for Dr. Xie, so he learned as much as possible about interventional radiology. Dr. Xie recalls one patient in particular with whom he was able to provide an early diagnosis of liver cancer and non-surgical treatment.
But the tumor continued to grow and the patient, who declined surgery, eventually died. Dr. Xie resolved to expand his knowledge of treatment options even further with a post-doctoral opportunity through the University of Rochester at the Center for Musculoskeletal Research in Rochester, N.Y.
Dr. Xie said that one of the vital opportunities he received when he arrived in the United States was guidance from several mentors, including Regis J. O’Keefe, MD, PhD, Edward M.Schwarz, PhD and Xinping Zhang, BMed, PhD.
“I really appreciate my mentors because they taught me the art of thinking, of bringing the problem from a clinical practice to the lab to solve it,” he said.
As he learned about basic science and how to seek financial support for research, Dr. Xie applied for Orthopaedic Research and Education Foundation (OREF) funding. His first two applications were denied, but, as in the rest of his career, Dr. Xie’s disappointment quickly turned to determination.
In 2012, he was awarded an OREF/Musculoskeletal Transplant Foundation (MTF) Research Grant to study parathyroid hormone (PTH) effects on intravenously-delivered stem cells during skeletal repair. His dream of becoming a clinician scientist became a reality.
“That was a huge opportunity for me as a junior faculty member. I could establish my own lab, complete my research, and generate preliminary data so that I could apply for a National Institutes of Health grant,” Dr. Xie said. “That opportunity shows why OREF is so important.”
Dr. Xie is passionate about speeding up the likelihood that patients directly benefit from the latest and most promising research. The great potential found in intravenous mesenchymal stem cell (IV-MSC) therapy for bone regeneration and non-invasive repair of fractures excited Dr. Xie, especially for older patients whose fractures increasingly are failing to heal after surgery due to non-union.
As an OREF/MTF Research Grant recipient, Dr. Xie hoped to better understand the origin of MSCs and how to enhance their activity in healing, particularly in environments prone to non-union. To do this, he developed an approach using MRIs to detect and track cells. He also determined that the addition of parathyroid hormone (PTH) can enhance MSC healing, especially in aging patients.
Prior research conducted by Dr. Xie and his research team had shown in a modified mouse model of fracture that IV-MSC therapy does have potential to repair and regenerate tissue during fracture healing1. FDA regulations, however, prevented Dr. Xie from exploring in clinical trials whether IV human MSCs (hMSCs) could aid fracture healing in humans. Dr. Xie and his research team needed to find an alternate, FDA-approved way to track hMSC activity throughout the fracture healing process.
Again using a mouse fracture model, Dr. Xie and his team tried labeling hMSCs with superparamagnetic iron oxide (Fe++) and tracking the labeled cells via a novel MRI method, but they found that the ex-vivo labeling caused the hMSCs to lose some of their “stemness.” He noted a loss in stem cell gene expression and lack of osteogenic differentiation of the labeled hMSCs at the fracture site in vivo.
So, with funding from the OREF/MTF research grant, Dr. Xie and his research team sought another method. Again using a mouse model, through MRI they looked for answers to three questions:
• Does culturing hMSCs with teriparatide, a recombinant form of PTH, in vitro prior to IV-MSC therapy reverse the negative effects of Fe++ labeling and allow the hMSCs to retain their stemness?
• Does using a non-metal labeling reagent allow hMSCs to retain their stemness?
• Does PTH act as an adjuvant that significantly increases hMSCs’ potential to proliferate prior to differentiation, target the injury, and sustain their pluripotent ability to differentiate into all of the cell types—osteoblasts, chondrocytes and adipocytes—needed for fracture healing?
Positive results from the OREF/MTF-funded study led Dr. Xie to conduct further research. Recently, he has been able to do the same research using large animals. He said the results are promising and that IV-hMSC therapy could one day be used on patients.
“Some patients, especially the elderly, due to infection or softer fibrotic tissue inserting between the fracture site, have fractures that result in a nonunion after treatment. Those bones cannot heal properly,” Dr. Xie said. “IV-hMSCs could be used to heal these difficult fractures.”
Opportunities for others
Because he has focused solely on research during his years in the United States., Dr. Xie said he has gained a deeper understanding about the importance of research for both clinicians and patients.
“As clinicians, we have lots of time to treat patients, but not to do the research. Also, researchers who are not clinicians usually don’t have access to patients. This is a gap,” he said. “OREF encourages physician scientists who close this gap by pursuing translational medicine.”
Dr. Xie never forgot the limitations he experienced as a young physician in China, and is now able to provide current Chinese medical students with some of the same opportunities he received. Together with his mentors Drs. O’Keefe and Schwarz, Dr. Xie established the University of Rochester China Institute to strengthen cooperative education, professional training, and research that improves human health.
Students focus on stem cell research, not only for tissue regeneration but also for treating carcinoma, spinal cord injuries, and other maladies that might benefit from the potential healing power of stem cells, Dr. Xie said.
“That’s why I’m so appreciative of OREF for giving me this opportunity to establish my own career. It not only benefits me but also other junior faculty both in the U.S. and in China,” said Dr. Xie. “If people understand the clinical potential of OREF-supported projects, then they understand the strength of OREF.”
Lisa Applegate is a contributing writer for OREF. She can be reached at email@example.com
1. Xie C, Reynolds D, Awad H, et al. Structural bone allograft combined with genetically engineered mesenchymal stem cells as a novel platform for bone tissue engineering. Tissue Eng. Mar 2007;13(3):435-445.