Paracrine Effect of Mesenchymal Stem Cells Derived from Human Adipose Tissue in Bone Regeneration

Abstract

Mesenchymal stem cell (MSC) transplantation has proved to be a promising strategy in cell therapy and regenerative medicine. Although their mechanism of action is not completely clear, it has been suggested that their therapeutic activity may be mediated by a paracrine effect. The main goal of this study was to evaluate by radiographic, morphometric and histological analysis the ability of mesenchymal stem cells derived from human adipose tissue (Ad-MSC) and their conditioned medium (CM), to repair surgical bone lesions using an in vivo model (rabbit mandibles). The results demonstrated that both, Ad-MSC and CM, induce bone regeneration in surgically created lesions in rabbit's jaws, suggesting that Ad-MSC improve the process of bone regeneration mainly by releasing paracrine factors. The evidence of the paracrine effect of MSC on bone regeneration has a major impact on regenerative medicine, and the use of their CM can address some issues and difficulties related to cell transplants. In particular, CM can be easily stored and transported, and is easier to handle by medical personnel during clinical procedures.

Adipose Derived Stem Cells Conditioned Media in Combination with Bioceramic-Collagen Scaffolds Improved Calvarial Bone Healing in Hypothyroid Rats

“…Two dimensional histological section analysis may fail to recognize small islands of newly formed bone in areas of defect. The increased amount of new tissue and bone cell numbers in the ADMSC-CM group could be explained by the fact of MSCs secretions such as IGF-1, TGF-β1, VEGF, HGF (Hepatocyte growth factor), BMP-1 (Bone morphogenetic protein-1), IL-6 (Interleukin), IL-3 (32, 50) regulate osteogenesis process as well as osteoblast proliferation and differentiation (17,51). Conditioned medium, in addition to stem cell mobilization into the injured site, induces stem cell differentiation into several lineages of mesenchymal tissue (24).…”

“…Mesenchymal stem cells (MSC), particularly that originated from bone marrow, are considered a suitable source for bone tissue engineering (16). However, MSC from adipose tissue (ADMSC) is a better choice for clinical application, because of minimally invasive procedure for fat harvesting, abundance and ease of MSC isolation and expansion in vitro (17). ADMSC is a multipotent cell that can differentiate into adipogenic, osteogenic, chondrogenic, myogenic, neurogenic and endothelial cells (18,19).…”

“…Since survival, differentiation and fate of transplanted MSC remains undetermined, it is suggested that paracrine effects of MSC secretion are the primary mechanism for tissue regeneration (29). Recent studies have demonstrated the effect of ADMSC-CM on tissue regeneration (17,30,31). Research has shown that MSC-CM contains large amounts of cytokines that are involved in bone regeneration such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) (32).…”

Regenerative Medicine: A New Paradigm in Bone Regeneration

“…For example, in an animal model of acute myocardial infarction, it was established that the MSCs implanted do not survive, and only 4.4% of grafted MSC could be found 1-2 weeks after transplantation [17], and MSC transplantation in a model of spinal cord injury in rats revealed that MSCs implanted disappeared from the host after 1-2 weeks [18]. It has been also reported that human adipose tissue-derived MSCs effectively induce bone regeneration in rabbit jaws, but they do not differentiate and do not survive more than 12 days in the site of implantation [21]. Recent reports have demonstrated that many of the therapeutic effects of MSCs can be mediated by the secretion of trophic factors, opening the possibility that direct administration of these mediators may replace the use of the cells in some instances [57].…”

“…The rationale was that after implantation or MSC injection, the cells would be able to colonize the injured site and differentiate into the appropriate lineages. This mechanism has now been challenged by a new paradigm to extend it to an alternative mechanism called paracrine effect, where MSCs secrete biologically active molecules which have beneficial effects on the injured tissues [9] by inhibiting fibrosis, apoptosis and inflammation [10,11] and promoting angiogenesis and tissue regeneration [19][20][21].…”