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Can a Single Dose of MSCs be an Effective Treatment for Osteoporosis?

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Review of “Systemic Mesenchymal Stromal Cell Transplantation Prevents Functional Bone Loss in a Mouse Model of Age-Related Osteoporosis” from Stem Cells Translational Medicine by Stuart P. Atkinson

The loss of bone volume and microarchitectural integrity in osteoporosis correlates to age-related changes in the proliferation and differentiation capacity of mesenchymal stromal cells (MSCs) [1, 2]. However, no clinical trials utilizing MSC transplantation as a therapeutic option exist or are recruiting, and existing animal studies have highlighted poor homing abilities of culture expanded MSC to bone as a major problem. 

Now, in a new study from William L. Stanford (Ottawa Hospital Research Institute, Ontario, Canada) and John E. Davies (University of Toronto, Canada), researchers show that MSCs can be extremely useful in the treatment of osteoporosis. Specifically, using the Sca-1 null mouse model of human type II osteoporosis [3], they show that minimally expanded unmodified donor MSCs can prevent the progression of osteoporosis-associated symptoms, and so may have relevance in the treatment of the human form of the disease [4].

After first attaining a pure and proliferative population of low passage patient MSCs with a robust osteogenic differentiation capacity [5], the authors injected a single transplant of around 2-4 million fluorescently labeled cells into the bloodstream of Sca-1 null mouse. In vivo imaging demonstrated the migration of donor MSCs to the long bones where they took residence in the bone marrow and compact bone in the short-term (two weeks). Further analysis at later time points provided evidence that rare donor MSCs engrafted long-term (24 weeks) in some, but not all, recipient mice.

But does this lead to a reversal of the reduced active bone formation observed in Sca-1 null mice during aging? Amazingly, at the 24 weeks stage, a single MSC transplantation recovered bone formation loss seen in Sca-1 null mice to levels similar to wild-type controls (See Figure). Furthermore, MSCs also boosted the bone surface occupied by osteoclasts (which absorbs bone tissue during growth and healing), the number of osteoclasts on the bone surface, and also mediated the appearance of a mineralization profile indicative of high bone turnover. Sca-1 null mice also normally present with aberrations in trabecular tissue microarchitecture (associated with human aging and osteoporosis [6, 7]), but the transplantation of MSCs reversed these aberrations and generated bone with characteristics similar to wild-type animals. 

The authors suggest that this provides a proof of concept for syngeneic MSC transplantation use to prevent or treat human age-related osteoporosis. The long-term results generated from a single cell transfusion certainly are dramatic, and the authors hope to next assess how MSC transplants can affect overall bone mechanics. 

References

  1. Bellantuono I, Aldahmash A, and Kassem M Aging of marrow stromal (skeletal) stem cells and their contribution to age-related bone loss. Biochim Biophys Acta 2009;1792:364-370.
  2. Muschler GF, Nitto H, Boehm CA, et al. Age- and gender-related changes in the cellularity of human bone marrow and the prevalence of osteoblastic progenitors. J Orthop Res 2001;19:117-125.
  3. Bonyadi M, Waldman SD, Liu D, et al. Mesenchymal progenitor self-renewal deficiency leads to age-dependent osteoporosis in Sca-1/Ly-6A null mice. Proc Natl Acad Sci U S A 2003;100:5840-5845.
  4. Kiernan J, Hu S, Grynpas MD, et al. Systemic Mesenchymal Stromal Cell Transplantation Prevents Functional Bone Loss in a Mouse Model of Age-Related Osteoporosis. Stem Cells Translational Medicine 2016;5:683-693.
  5. Short BJ, Brouard N, and Simmons PJ Prospective isolation of mesenchymal stem cells from mouse compact bone. Methods Mol Biol 2009;482:259-268.
  6. Holzer A, Pietschmann MF, Rosl C, et al. The interrelation of trabecular microstructural parameters of the greater tubercle measured for different species. J Orthop Res 2012;30:429-434.
  7. Jiang Y, Zhao J, Liao EY, et al. Application of micro-CT assessment of 3-D bone microstructure in preclinical and clinical studies. J Bone Miner Metab 2005;23 Suppl:122-131.