BMP4-Expressing Muscle-Derived Stem Cells Differentiate into Osteogenic Lineage and Improve Bone Healing in Immunocompetent Mice

Abstract

Recent advances in molecular biology have led the way for novel approaches to improve bone healing. The ideal growth factor, vector, and delivery systems for producing bone in an immune competent animal model, however, have yet to be identified. Using a retrovirus encoding BMP4 and recently isolated muscle-derived stem cells (MDSCs), we demonstrated the following: MDSCs undergo osteogenic differentiation in response to BMP4 in a dose-dependent manner; retrovirus encoding BMP4 can efficiently transduce MDSCs, both enhancing osteogenic differentiation and inhibiting myogenic differentiation; transduced MDSCs can produce high levels of functional BMP4 as they differentiate toward an osteogenic lineage; allogeneic transduced MDSCs can induce robust de novo bone formation in immunocompetent mice despite the presence of an immune reaction, demonstrating the ability of this retroviral-BMP4-muscle construct to provide sufficient stimuli for osteoinduction in vivo; MDSCs appear to deliver BMP4, respond to the human BMP4 in an autocrine manner, and actively participate in bone formation, thus serving both osteoinductive and osteoproductive roles; and the BMP4-expressing MDSCs can induce bone formation and improve bone healing in a critical-sized skull defect in immunocompetent mice. Therefore, we believe that technology based on the MDSCs and vector system has great potential for promoting bone healing in a variety of musculoskeletal conditions.

Regenerative medicine in orthopaedic surgery

“…16,19 Furthermore, they can undergo multilineage differentiation toward skeletal muscle, bone, cartilage, and neural, endothelial, and hematopoietic tissues. 15,16,[20][21][22][23][24][25][26] They are found in murine skeletal muscle at a ratio of 1 in 100,000 cells, 16 a ratio similar to that of adult mesenchymal stem cells (MSCs) isolated from bone marrow aspirates. 5 Although this suggests that a large muscle biopsy will be required to isolate sufficient cells for therapeutic applications, this limitation is overcome by the fact that MDSCs and other stem cells are easily expanded in vitro without loss of progenitor characteristics.…”

“…21 MDSCs have also led to bone formation and healed critical-sized calvarial and long bone defects when genetically engineered to express BMP2 or BMP4. 15,[22][23][24][25][26] They were found within the newly formed bone and some co-localized with osteocalcin, suggesting that the cells differentiated into osteogenic cells. 15 …”

Delayed administration of adenoviral BMP-2 vector improves the formation of bone in osseous defects

“…1,2 A growing literature describes the responsiveness of bone to transfer of osteogenic cDNAs encoding bone morphogenetic proteins (BMPs) -2, -4, -6, -7 and -9. [3][4][5][6][7][8][9] The properties of those BMPs have many potential clinical applications, such as to accelerate the healing of fractures, improve the repair of non-unions and segmental defects, enhance spinal fusion and provide better fixation for prosthetic implants.…”

The influence of sex on the chondrogenic potential of muscle‐derived stem cells: Implications for cartilage regeneration and repair

“…MDSCs could potentially be a novel cell source for cartilage tissue engineering. They are known to have multilineage differentiation potential, including the ability to differentiate into skeletal muscle, bone, neural, endothelial, and hematopoietic tissue (12,(18)(19)(20)(21)(22)(23). We have previously shown that muscle-derived cells, including MDSCs, can undergo chondrogenesis in vivo and in vitro (24,25).…”