Accelerated Bone Regeneration via Transplant of Engineered Perivascular Stem Cells

Reprogramming stem or progenitor cells to adjust their behavior is growing in popularity as an approach to regenerative medicine. The large reductions in the cost of exploring cellular mechanisms achieved over the past twenty years mean that there is now a much greater understanding of relevant mechanisms, as well as a greater capacity to discover novel targets of interest for specific goals in altered cell behavior. The more straightforward outcome in this part of the field is simply to increase stem cell activity, to reduce the amount of time these cells spend quiescent rather than actively supplying tissue with new daughter somatic cells to assist in repair. As today's open access paper illustrates, there are certainly other options on the table, however.

Many stem cell populations are multipotent, meaning that they are capable of generating several different types of somatic cell. If only one type is desired for regeneration, then steering the stem cells into creating only that type for a while is effectively the same thing as speeding up their activity in general. Researchers here do this for cells that create both fat and bone tissue, identifying a regulatory protein, WISP1, that determines which is produced. These cells can then be harvested, engineered to express a higher level of WISP1, and used as a cell therapy to accelerate bone regrowth. That, at least, is the hope, given the initial evidence here from an animal study.

Stem Cell Signal Drives New Bone Building

Stem cells have the potential to develop into a variety of cell types including those that make up living tissues, such as bones. Scientists have long sought ways to manipulate the growth and developmental path of these cells, to repair or replace tissue lost to disease or injury. Previous studies showed that a particular type of stem cell - perivascular stem cells - had the ability to become either bone or fat, and that the protein WISP-1 plays a key role in directing these stem cells.

In a new study, researchers engineered stem cells collected from patients to block the production of the WISP-1 protein. Looking at gene activity in the cells without WISP-1, they found that four genes that cause fat formation were turned on 50-200 percent higher than control cells that contained normal levels of the WISP-1 protein. The team then engineered human fat tissue stem cells to make more WISP-1 protein than normal, and found that three genes controlling bone formation became twice as active as in the control cells, and fat driving genes such as peroxisome proliferator-activated receptor gamma (PPARĪ³) decreased in activity in favor of "bone genes" by 42 percent.

The researchers next designed an experiment to test whether the WISP-1 protein could be used to improve bone healing in rats that underwent a type of spinal fusion. The researchers mimicked the human surgical procedure in rats, but in addition, they injected - between the fused spinal bones - human stem cells with WISP-1 turned on. After four weeks, the researchers studied the rats' spinal tissue and observed continued high levels of the WISP-1 protein. They also observed new bone forming, successfully fusing the vertebrae together, whereas the rats not treated with stem cells making WISP-1 did not show any successful bone fusion during the time the researchers were observing.

WISP-1 drives bone formation at the expense of fat formation in human perivascular stem cells

The vascular wall within adipose tissue is a source of mesenchymal progenitors, referred to as perivascular stem/stromal cells (PSC). Those factors that promote the differentiation of PSC into bone or fat cell types are not well understood. Here, we observed high expression of WISP-1 among human PSC in vivo, after purification, and upon transplantation in a bone defect. Next, modulation of WISP-1 expression was performed, using WISP-1 overexpression, WISP-1 protein, or WISP-1 siRNA. Results demonstrated that WISP-1 is expressed in the perivascular niche, and high expression is maintained after purification of PSC, and upon transplantation in a bone microenvironment.

In vitro studies demonstrate that WISP-1 has pro-osteogenic/anti-adipocytic effects in human PSC, and that regulation of BMP signaling activity may underlie these effects. In summary, our results demonstrate the importance of the matricellular protein WISP-1 in regulation of the differentiation of human stem cell types within the perivascular niche. WISP-1 signaling upregulation may be of future benefit in cell therapy mediated bone tissue engineering, for the healing of bone defects or other orthopedic applications.


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