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A Safe and Rapid Strategy for Improved Bone Defect Repair by Bone Marrow Stem Cells

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Review of “Rapid Osteogenic Enhancement of Stem Cells in Human Bone Marrow Using a Glycogen-Synthase-Kinase-3-beta Inhibitor Improves Osteogenic Efficacy In Vitro and In Vivo” from STEM CELLS Translational Medicine by Stuart P. Atkinson

While bone grafts remain the best therapy for non-union bone defects, donor site morbidity and the limited availability of graft material represent significant obstacles for this treatment option [1]. Human bone marrow (BM)-derived progenitor and stem cells administered with an appropriate scaffold represents a potentially exciting alternative treatment option [2], but only if we can discover a safe and rapid strategy to enhance the relatively low inherent osteogenic potential of BM.

Interestingly, a previous STEM CELLS study from Janeczek et al. [3] established that activating the WNT signaling `pathway in BM led to the generation of an osteogenically enhanced subset of stem cells. Now, new research from the laboratory of Carl Gregory (Texas A&M Health Science Center, USA) published in STEM CELLS Translational Medicine now demonstrates that WNT stimulation of human BM via a rapid exposure to a previously tested GSK3β-inhibitor [4] significantly increases osteogenic potential and improves therapeutic outcomes in a rat spinal fusion model [5].

Clough et al. first considered responses of human mesenchymal stem cells (hMSCs) present in the BM to the GSK3β-inhibitor (2′Z,3′E)-6-bromoindirubin-3′-oxime (BIO) at a concentration of 800 nM, given that hMSCs represent presumptive precursors of osteoblasts. Interestingly, transient BIO exposure (1–2 hours) prompted accelerated WNT signaling in hMSCs and stimulated the expression of early osteogenic markers, such as the osteogenic master-regulator Runx2.

However, the need for the rapid point-of-care clinical application of BM stem cells for bone defect repair will not allow for the purification of hMSCs from the BM, and so, the authors assessed the effect of transient BIO exposure to whole BM samples. Encouragingly, whole BM reacted similarly to purified hMSCs, as evidenced by the upregulation of Runx2 and the sustained osteogenic enhancement of the plastic-adherent hMSC-containing BM subpopulation. Furthermore, transplantation of BIO-treated BM cells combined with an extracellular matrix scaffold into a rat spinal fusion model led to the formation of stronger and denser bone fusion masses than vehicle-treated control BM samples.

These encouraging data suggest that transient BIO treatment may represent a safe and rapid strategy to enhance the osteogenic potential of patient BM stem cells, a bone defect repair approach that the authors believe is a faster path to clinical translation than the treatment of purified and ex vivo-amplified hMSCs.

To discover more regarding new stem cell therapies for improved bone defect repair, stay tuned to the Stem Cells Portal!

References

  1. de Boer HH, The history of bone grafts. Clin Orthop Relat Res 1988:292-8.
  2. Hernigou P, Poignard A, Beaujean F, et al., Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am 2005;87:1430-7.
  3. Janeczek AA, Tare RS, Scarpa E, et al., Transient Canonical Wnt Stimulation Enriches Human Bone Marrow Mononuclear Cell Isolates for Osteoprogenitors. STEM CELLS 2016;34:418-430.
  4. Damiens E, Baratte B, Marie D, et al., Anti-mitotic properties of indirubin-3′-monoxime, a CDK/GSK-3 inhibitor: induction of endoreplication following prophase arrest. Oncogene 2001;20:3786.
  5. Clough BH, Zeitouni S, Krause U, et al., Rapid Osteogenic Enhancement of Stem Cells in Human Bone Marrow Using a Glycogen‐Synthease‐Kinase‐3‐Beta Inhibitor Improves Osteogenic Efficacy In Vitro and In Vivo. STEM CELLS Translational Medicine 2018;7:342-353.