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Diabetes Inhibits Bone Regeneration by Autologous Mesenchymal Stem Cell-derived Exosomes

Review of “Impaired bone regenerative effect of exosomes derived from bone marrow mesenchymal stem cells in type 1 diabetes” from STEM CELLS Translational Medicine by Stuart P. Atkinson 

Reduced bone mineral density and bone quality in patients with type 1 diabetes (T1DM) lead to a higher risk of hip fracture when compared to healthy patients [1]. Bone marrow-derived mesenchymal stem cells (MSCs) can differentiate into osteoblasts, which can synthesize proteoglycans, type I collagen, and other non-collagenous proteins for bone matrix mineralization [2, 3] and therefore represent a potential treatment option for bone injuries in T1DM patients. However, studies have established that that T1DM/hyperglycemia negatively influence the osteogenic potential of MSCs [4, 5].

Recently, researchers from the laboratories of Yimin Chai and Jia Xu (Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, PR China) sought to compare the osteogenic potential of exosomes derived from MSCs from T1DM and healthy donors in the hope of developing a cell-free approach to bone regeneration. Reporting in STEM CELLS Translational Medicine, Zhu et al. employed a rat model of diabetes to establish that the autologous transplantation of MSC exosomes for bone regeneration purposes may be inappropriate for some patients [6].

Following isolation of MSCs from rats with and without streptozotocin‐induced diabetes, the authors collected exosomes from both cell populations via ultracentrifugation and carried out various comparative assessments to elucidate any differences prompted by diabetes. Interestingly, while both sets of exosomes enhanced the osteogenic differentiation of MSCs and promoted the angiogenic activity of human umbilical vein endothelial cells, diabetic rat MSC exosomes exhibited a more muted effect. Of note, the proangiogenic effect of MSC exosomes may foster the development of adequate vasculature, which is an important means of promoting bone development and regeneration [7]. Additionally, assessment of the in vivo regenerative capacity of MSC exosomes in a rat calvarial defect model revealed that while both sets of exosomes promoted bone regeneration and neovascularization, diabetic rat MSC exosomes again displayed a reduced effect when compared to those derived from a healthy donor MSCs.

While the authors establish the reduction in the therapeutic potential of diabetic rat MSC exosomes, thereby suggesting that the relative success of autologous transplantation of MSC exosomes in bone regeneration depends on the condition of the patient, they note certain limitations to their study. To address these limitations, the authors hope to next describe the mechanism controlling pro‐osteogenic and pro‐angiogenic effects of MSC exosomes from healthy donors and widen their research to human patient samples.

For more on the pro-regenerative power of exosomes and the consequences of diabetes on stem cells, stay tuned to the Stem Cells Portal!

References

  1. Sellmeyer DE, Civitelli R, Hofbauer LC, et al., Skeletal Metabolism, Fracture Risk, and Fracture Outcomes in Type 1 and Type 2 Diabetes. Diabetes 2016;65:1757.
  2. Garg P, Mazur MM, Buck AC, et al., Prospective Review of Mesenchymal Stem Cells Differentiation into Osteoblasts. Orthopaedic Surgery 2017;9:13-19.
  3. Hadjiargyrou M and O'Keefe RJ, The Convergence of Fracture Repair and Stem Cells: Interplay of Genes, Aging, Environmental Factors and Disease. Journal of Bone and Mineral Research 2014;29:2307-2322.
  4. Filion TM, Skelly JD, Huang H, et al., Impaired osteogenesis of T1DM bone marrow-derived stromal cells and periosteum-derived cells and their differential in-vitro responses to growth factor rescue. Stem Cell Research & Therapy 2017;8:65.
  5. Cramer C, Freisinger E, Jones RK, et al., Persistent High Glucose Concentrations Alter the Regenerative Potential of Mesenchymal Stem Cells. Stem Cells and Development 2010;19:1875-1884.
  6. Zhu Y, Jia Y, Wang Y, et al., Impaired Bone Regenerative Effect of Exosomes Derived from Bone Marrow Mesenchymal Stem Cells in Type 1 Diabetes. STEM CELLS Translational Medicine 2019;8:593-605.
  7. Filipowska J, Tomaszewski KA, Niedźwiedzki Ł, et al., The role of vasculature in bone development, regeneration and proper systemic functioning. Angiogenesis 2017;20:291-302.