Dr. Xie uses MRI results to track hMSCs' potential to proliferate prior to differentiation, target injury, and sustain their pluripotent ability to differentiate into all of the cell types needed for fracture healing.
Courtesy of Chao Xie, MD

AAOS Now

Published 12/1/2016
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Lisa Applegate

Turning Obstacles into Opportunities

OREF grant recipient investigates noninvasive 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. As a first-year medical student, Dr. Xie experienced personal frustration when his father received a late diagnosis of cancer because computed tomography scans were not widely available 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 illnesses without being able to treat them 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 for whom he was able to provide an early diagnosis of liver cancer and nonsurgical 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 postdoctoral 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 funding from the Orthopaedic Research and Education Foundation (OREF). 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 being 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."

Translational research
Dr. Xie is passionate about speeding up the likelihood that patients directly benefit from the latest and most promising research. He is excited by the great potential found in intravenous mesenchymal stem cell (IV-MSC) therapy for bone regeneration and noninvasive repair of fractures, especially for older patients whose fractures fail to heal after surgery due to nonunion.

As an OREF/MTF Research Grant recipient, Dr. Xie hopes to better understand the origin of MSCs and how to enhance their activity in healing, particularly in environments prone to nonunion. To do this, he developed an approach using magnetic resonance imaging (MRI) to detect and track cells. He also determined that the addition of PTH can enhance fracture healing, especially in aging patients.

Using a modified mouse model, Dr. Xie and his research team had previously shown that IV-MSC therapy has potential to repair and regenerate tissue during fracture healing. Under current regulations issued by the U.S. Food and Drug Administration, Dr. Xie could not conduct a clinical trial exploring whether human MSCs (hMSCs) delivered intravenously 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.

Dr. Xie and his team tried labeling hMSCs with superparamagnetic iron oxide (Fe++) and tracking the labeled cells in a mouse fracture model using a novel MRI method. They quickly found that the ex vivo labeling caused the hMSCs to lose some of their unique qualities. In vivo, labeled hMSCs seemingly lost stem cell gene expression and osteogenic differentiation at the fracture site.

So, with funding from the OREF/MTF research grant, Dr. Xie and his research team sought another method. Again using a mouse model and MRI, they looked for answers to the following 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 enable the hMSCs to retain their qualities?
  • Does using a nonmetal labeling reagent enable hMSCs to retain their qualities?
  • Does PTH act as an adjuvant that significantly increases the potential of hMSCs 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, have fractures that result in a nonunion after treatment due to infection or softer fibrotic tissue inserting between the fracture site. 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."

Remembering the limitations he experienced as a young physician in China, Dr. Xie now provides 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 carcinomas, 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 United States and in China," said Dr. Xie. 

Lisa Applegate is a contributing writer for OREF. She can be reached at communications@oref.org

Reference:
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 2007;13(3):435–445.