New protocol could signal shift in bone regenerative medicine


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A new, safe and efficient way to coax stem cells into bone cells is reported in a recently published article from STEM CELLS Translational Medicine (SCTM).
DURHAM, N.C., Jan. 6, 2020 /PRNewswire-PRWeb/ -- A new, safe and efficient way to coax stem cells into bone cells is reported in a recently published article from STEM CELLS Translational Medicine (SCTM). The protocol, developed by researchers at the University of Sydney, Australian Research Centre (ARC) for Innovative BioEngineering, could lead to a shift in the treatment of bone regenerative medicine.

Large bone defects and loss due to cancer or trauma can result in scar tissue that impairs the bones' ability to repair and regenerate. The current gold standard therapy, autografting, has inherent drawbacks, including limited availability and donor site morbidity. This leaves researchers seeking an alternative source of bone cells — and makes bone tissue engineering a growing field with considerable translational potential.

"The success of induced pluripotent stem cell (iPSC) technology to reprogram fibroblasts into progenitor cells of various lineages offers an exciting route for tissue repair and regeneration," said Zufu Lu, Ph.D., a member of the University of Sydney's Biomaterials and Tissue Engineering Research Unit and a research associate at the ARC for Innovative BioEngineering. He is a co-lead investigator of the SCTM study, along with Professor Hala Zreiqat, Ph.D., head of the research unit and director of the ARC Training Centre for Innovative BioEngineering.

"However, while iPSC technology represents a potentially unlimited source of progenitor cells and allows patients to use their own cells for tissue repair and regeneration — thus posing little or no risk of immune rejection – the technology has several constraints. Among them are the requirement for complex reprogramming using the Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc). To add to the complexity, specific stimuli are required to direct iPSCs to re-differentiate to progenitor cells of the lineage of interest.

"In addition," Dr. Lu said, "any remaining iPSCs pose the risk of tumors following implantation."
One potential way around this, as demonstrated by recent studies, is through the direct reprogramming of fibroblasts into bone cells. "Fibroblasts are morphologically similar to osteoblasts. Their similar transcriptomic profiles led us to hypothesize that distinct factors produced by osteoblasts may be capable of coaxing fibroblasts to become osteoblast-like cells," Prof. Zreiqat said.

Previous studies aimed at using fibroblasts to produce various cell types relied on the genetic manipulation of one or more transcription regulators. But just as with iPSCs, reprogramming fibroblasts in this manner has its own inherent technical and safety issues. The Lu-Zreiqat team, however, surmised that an approach employing natural factors might just allow better control over reprogramming and improve the safety.

"Unlike genetic reprogramming, chemical induction of cell reprogramming is generally rapid and reversible, and is also more amenable to control through factor dosage and/or combinations with other molecules," Dr. Lu explained.

The team initially determined that media conditioned by human osteoblasts can induce reprogramming of human fibroblasts to functional osteoblasts. "Next," said Prof. Zreiqat, "our proteomic analysis identified a single naturally bioactive protein, insulin growth factor binding protein-7 (IGFBP7), as being significantly elevated in media conditioned with osteoblasts, compared to those with fibroblasts."
This led them to test IGFBP7's ability as a transcription factor. They found it, indeed, successfully induced a switch from fibroblasts to osteoblasts in vitro. They next tested it in a mouse model — and once again experienced success when the fibroblasts produced mineralized tissue. The switch was associated with senescence and dependent on autocrine IL-6 signaling.
"The approach we describe in our study has significant advantages over other commonly used cell sources including iPSCs and adult mesenchymal stem cells," Dr. Lu and Prof Zreiqat concluded.
"Bone tissue engineering is a growing field where cell therapies have considerable translational potential, but current cell-based approaches face limitations," said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. "The novel observation described in this study could potentially lead to a shift in the current paradigm of bone regenerative medicine."