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Local Transplantation of BM-MSCs Improves Cell Therapy for Osteogenesis Imperfecta

Review of “Engraftment of Skeletal Progenitor Cells by Bone Directed Transplantation Improves Osteogenesis Imperfecta Murine Bone Phenotype” from STEM CELLS by Stuart P. Atkinson

Approaches to the treatment of osteogenesis imperfecta, a genetic disorder associated with defective bone matrix and high risks of fracture [1], include cell-based therapies; however, low cell engraftment and a lack of the conclusive detection of cell differentiation into the osteoblast lineage represent fundamental limitations to many cell therapies.

Researchers led by Ivo Kalajzic (UConn Health, Farmington, CT, USA) previously reported the engraftment potential of locally transplanted (intra-bone [2]) bone marrow-derived mesenchymal stem cells (BM-MSCs) in a proof‐of‐concept study in an osteogenesis imperfecta mouse model [3]. To investigate if this strategy fostered improvements in bone morphology, structure, and strength or engrafted donor cell phenotype, the team developed BM-MSCs that expressed one fluorescent genetic markers to track BM-MSCs and their progeny [4, 5], and another that tracked the differentiation of BM-MSCs into osteoblasts and osteocytes [6]. The team’s findings, reported recently in STEM CELLS [7], now establish that locally transplanted BM-MSCs continually give rise to osteoblasts and promote improvements to bone morphology and mechanical properties in an osteogenesis imperfecta mouse model.

Sinder et al. locally transplanted reporter BM-MSCs into the femurs of sublethally irradiated osteogenesis imperfecta model mice; at one month, they found BM-MSC-derived osteoblasts made up around 20% of the endosteal surface, suggesting robust engraftment. Indeed, follow-up studies at three- and six-months post-transplantation provided evidence of long‐term engraftment of BM-MSCs in the bone marrow as osteoprogenitors, with both in vitro and in vivo secondary transplantation studies in osteogenesis imperfecta model mice establishing their ongoing ability to differentiate into osteoblasts. Furthermore, assessments made at three months provided evidence that the local administration of BM-MSCs, their engraftment, and differentiation fostered improved bone microarchitecture and biomechanics via improvements in cortical thickness, the polar moment of inertia, bone strength, and stiffness. 

Overall, these data suggest that the local administration of BM-MSCs can support the long-term generation of osteoblast progenitors, and hence osteoblasts and osteocytes, in osteogenesis imperfecta mice for at least six months, leading to improved bone structure and strength during that time. While intra-bone administration of BM-MSCs leads to protracted and durable therapeutic effects, the authors do note that a local treatment for a systemic disorder is far from ideal. However, osteogenesis imperfecta patients undergo many orthopedic procedures, thereby suggesting that the intra-bone BM-MSCs administration may be integrated into planned surgical procedures.

For more on how the local transplantation can improve BM-MSC therapy of osteogenesis imperfecta, stay tuned to the Stem Cells Portal.

References

  1. Forlino A, Cabral WA, Barnes AM, et al., New perspectives on osteogenesis imperfecta. Nature Reviews Endocrinology 2011;7:540-557.
  2. Li F, Wang X, and Niyibizi C, Bone marrow stromal cells contribute to bone formation following infusion into femoral cavities of a mouse model of osteogenesis imperfecta. Bone 2010;47:546-555.
  3. Pauley P, Matthews BG, Wang L, et al., Local transplantation is an effective method for cell delivery in the osteogenesis imperfecta murine model. International Orthopaedics 2014;38:1955-1962.
  4. Grcevic D, Pejda S, Matthews BG, et al., In Vivo Fate Mapping Identifies Mesenchymal Progenitor Cells. STEM CELLS 2012;30:187-196.
  5. Matthews BG, Grcevic D, Wang L, et al., Analysis of αSMA-Labeled Progenitor Cell Commitment Identifies Notch Signaling as an Important Pathway in Fracture Healing. Journal of Bone and Mineral Research 2014;29:1283-1294.
  6. Kalajzic I, Kalajzic Z, Kaliterna M, et al., Use of Type I Collagen Green Fluorescent Protein Transgenes to Identify Subpopulations of Cells at Different Stages of the Osteoblast Lineage. Journal of Bone and Mineral Research 2002;17:15-25.
  7. Sinder BP, Novak S, Wee NKY, et al., Engraftment of skeletal progenitor cells by bone-directed transplantation improves osteogenesis imperfecta murine bone phenotype. STEM CELLS 2020;38:530-541.