Therapeutic potential of adult bone marrow-derived mesenchymal stem cells in diseases of the skeleton

Abstract

Mesenchymal stem cells (MSCs) are the most popular among the adult stem cells in tissue engineering and regenerative medicine. Since their discovery and functional characterization in the late 1960s and early 1970s, MSCs or MSC-like cells have been obtained from various mesodermal and non-mesodermal tissues, although majority of the therapeutic applications involved bone marrow-derived MSCs. Based on its mesenchymal origin, it was predicted earlier that MSCs only can differentiate into mesengenic lineages like bone, cartilage, fat or muscle. However, varied isolation and cell culturing methods identified subsets of MSCs in the bone marrow which not only differentiated into mesenchymal lineages, but also into ectodermal and endodermal derivatives. Although, true pluripotent status is yet to be established, MSCs have been successfully used in bone and cartilage regeneration in osteoporotic fracture and arthritis, respectively, and in the repair of cardiac tissue following myocardial infarction. Immunosuppressive properties of MSCs extend utility of MSCs to reduce complications of graft versus host disease and rheumatoid arthritis. Homing of MSCs to sites of tissue injury, including tumor, is well established. In addition to their ability in tissue regeneration, MSCs can be genetically engineered ex vivo for delivery of therapeutic molecule(s) to the sites of injury or tumorigenesis as cell therapy vehicles. MSCs tend to lose surface receptors for trafficking and have been reported to develop sarcoma in long-term culture. In this article, we reviewed the current status of MSCs with special emphasis to therapeutic application in bone-related diseases.

Figure 1

Enhancing bone homing potential of culture expanded MSC: MSC loses CXCR4 receptors ex vivo, thus fail to respond in vivo to a SDF-1α gradient released by the bone marrow cells at the fractured site (s). Pre-treatment of MSC with a cytokine cocktail restores CXCR4 surface expression by the MSC and efficiently migrate to bone. Bone homing capacity of the MSC can be further improved via transduction of α4 integrin (absent in MSC), which dimerizes with β1 integrin (abundant in MSC). α4β1 integrin is expressed on the surface of the MSC, which resulted in efficient transendothelial migration and bone homing via interaction with its ligands, VCAM-1(CD-106) and fibronectin.

Figure 2

Therapeutic potential of naïve MSC in osteolytic bone metastasis. (A) Immunostaining indicated murine and human MSC constitutively express osteoprotegerin in culture (green fluorescence). (B) Growth of bone metastatic prostate cancer cells (PC3) in the mouse tibia generates severe osteolytic lesions. (C) MSC expressing OPG prevents bone loss via inhibition of osteoclastogenesis which is required by the tumor cells for growth in bone. (D) Besides, MSCs formed woven bone around the tumor nests (*) which further reduced tumor progression. Bone sections were stained with Goldner's trichrome stain and collagen is stained green.