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Bmi1 Overexpression in MSCs - A Novel Means to Treat Aging-related Disease?

Review of “Bmi1 Overexpression in Mesenchymal Stem Cells Exerts Anti‐Aging and Anti‐Osteoporosis Effects by Inactivating p16/p19 Signaling and Inhibiting Oxidative Stress” from STEM CELLS by Stuart P. Atkinson

Research from the group of Dengshun Miao (Nanjing Medical University, Nanjing, China) previously established that the loss of the Bmi1 polycomb ring finger oncogene prompted a reduction in the self-renewal and osteoblastic differentiation propensity of mesenchymal stem cells (MSCs) and premature osteoporosis in mice [1]. Their follow up studies discovered that mice with lymphocytes that specifically overexpress Bmi1 possessed an improved osteogenic microenvironment that stimulated skeletogenesis [2]. 

Now, the team returns with a new STEM CELLS article in which they sought to discover whether overexpression of Bmi1 in MSCs in vivo could stimulate skeletogenesis and rescue premature osteoporosis caused by a global deficiency in Bmi1 levels [3]. The authors took inspiration from studies in human MSCs that established how BMI1 overexpression increased proliferation [4] and enhanced osteogenesis upon differentiation [5] and they hope that their new findings, demonstrating that Bmi1 overexpression exerts anti‐aging and anti‐osteoporosis effects, may permit the development of enhanced MSC-based therapeutic approaches.

To explore whether Bmi1-overexpressing MSCs had the potential to stimulate skeletal development and rescued Bmi1 deficiency‐induced osteoporosis, Chen et al. generated Bmi-null mice that possessed MSCs expressing Bmi1 driven by the Prx1 gene, a mesenchymal lineage gene, and then compared their skeletal phenotypes with Bmi1-null and wild‐type mice using a range of methodologies. Encouragingly, Bmi1-overexpressing MSCs promoted accelerated skeletal growth and osteoblastic bone formation by the stimulation of bone marrow MSC osteogenesis and largely reversing the skeletal growth retardation and osteoporosis associated with systemic Bmi1 deficiency. 

However, the authors also discovered that Bmi1 overexpression in MSCs also partially reversed Bmi1 deficiency‐induced systemic growth retardation and premature aging by inhibiting oxidative stress by of antioxidant enzyme gene expression and reducing and p16/p19 signaling. 

While the authors suggest that the incomplete reversal of the Bmi1-loss induced phenotype after Bmi1 expression in MSCs suggests that the maintenance of skeletal homeostasis requires cooperation between osteogenic cells and osteogenic microenvironmental cells, they do believe that Bmi1 overexpression may provide an exciting new means to potentiate MSCs as part of enhanced anti-aging and anti-osteoporosis therapies.

For more on MSC-based therapies for aging, osteoporosis, and other related disorders, and how Bmi1 overexpression in MSCs may provide a novel means to treat aging-related disease, stay tuned to the Stem Cells Portal!

References

  1. Zhang H-W, Ding J, Jin J-L, et al., Defects in mesenchymal stem cell self-renewal and cell fate determination lead to an osteopenic phenotype in Bmi-1 null mice. Journal of Bone and Mineral Research 2010;25:640-652.
  2. Zhou X, Dai X, Wu X, et al., Overexpression of Bmi1 in Lymphocytes Stimulates Skeletogenesis by Improving the Osteogenic Microenvironment. Scientific Reports 2016;6:29171.
  3. Chen G, Zhang Y, Yu S, et al., Bmi1 Overexpression in Mesenchymal Stem Cells Exerts Antiaging and Antiosteoporosis Effects by Inactivating p16/p19 Signaling and Inhibiting Oxidative Stress. STEM CELLS 2019;37:1200-1211.
  4. Lee JY, Yu KR, Kim HS, et al., BMI1 inhibits senescence and enhances the immunomodulatory properties of human mesenchymal stem cells via the direct suppression of MKP-1/DUSP1. Aging (Albany NY) 2016;8:1670-89.
  5. Becker M, Potapenko T, Niklaus A, et al., Polycomb Protein BMI1 Regulates Osteogenic Differentiation of Human Adipose Tissue-Derived Mesenchymal Stem Cells Downstream of GSK3. Stem Cells and Development 2016;25:922-33.