A step closer to stem cell therapies for bone disease

Controlling a protein’s levels could guide stem cell differentiation for treatment of bone disease.

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DAVID MARCHAL / ALAMY STOCK PHOTO

As we get older, our bodies can struggle to generate the right balance of stem cells that are committed to maintaining bone formation and bone structure. This can contribute to the development of bone-related diseases. Now, researchers in Saudi Arabia have uncovered the molecular mechanisms behind bone marrow stem cell differentiation into bone tissue and fat cells. Their insights could inform the development of future regenerative therapies for age-related bone diseases.

Stem cells located in the bone marrow, known as human bone marrow stromal cells (hBMSCs), have potential for use in multiple therapies. But scientists must first understand what determines their differentiation into osteoblasts (bone cells) or adipocytes (fat cells) so they can be guided to generate the correct type.

Amer Mahmood and co-workers at King Saud University in Riyadh, together with researchers across Saudi Arabia and Denmark, highlighted the role of the low-density lipoprotein receptor-related protein 3, or LRP3, in hBMSC differentiation. The LRP3 protein is involved in multiple cellular processes in the body and is expressed in many human tissues, especially skeletal muscles.

Mahmood’s team generated two clones derived from hBMSCs: one that exhibited enhanced osteoblast differentiation potential and one with reduced potential. Using gene profiling techniques, the team analysed the genetic differences between the clones to precisely determine the genes and associated proteins involved in the differentiation process.

They found that the enhanced clone exhibited much higher levels of LRP3 than the reduced potential clone. Further, they showed that the LRP3 protein acts as a molecular switch determining the differentiation of hBMSCs into osteoblasts. LRP3 itself is regulated by a small molecule called miR-4739, a microRNA known to play a key role in bone biology. Further experiments on the stem cell lines showed that the over-expression of miR-4739 led to reduced levels of LRP3. This prompted hBMSCs to change into fat cells instead of bone cells.

“We propose the use of miR-4739 mimics or inhibitors to fine-tune the commitment of hBMSCs to [bone or fat cells], with potential application in regenerative medicine,” state the authors in their paper, recently published in Stem Cell Research. Using micro-RNA molecules in this way to stimulate hBMSCs into required cell types and boost bone cell numbers could prove invaluable in the treatment of bone-related diseases. Elsafadi, M., Manikandan, M., Alajez, N.M.,

References

  1. Elsafadi, M., Manikandan, M., Alajez, N.M., Hamam, R., Dawud, R.A., et al. Micro-RNA-4739 regulates osteogenic and adipocytic differentiation of immortalized human bone marrow stromal cells via targeting LRP3. Stem Cell Research 20, 94-104 (2017). | article

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