Bone engineering using stem cells has enormous clinical potential for the treatment of congenital bone defects such as cleft palates. Successful bone healing has recently been reported in animal models using scaffolds coated with biomimetic apatites and seeded with stem cells. With its osteogenic capacity, the adipose-derived stem cell (ASC) may represent an additional stem cells population appropriate for such a model system. Current strategies for inducing stem cells to form bone in vivo involve combining them with growth factors like BMP2. However, the use of BMP2 may not be recommended in very young children with cleft defects due to the potential of unwanted bone formation, suggesting that an alternative mechanism for stimulating stem cells to heal bone will be necessary. Preliminary analysis of ASCs suggests that MAPK kinases may be involved in mediating ASC osteogenesis. Therefore, we propose that the MAPK pathway may be specifically manipulated in ASCs to promote their in vivo osteogenic capacity without the need for growth factors using an adhesion-based mechanism and customized apatite coatings. While animals models for cleft repair using stem cells are beginning to emerge - there is little to no experimental and clinical data utilizing human stem cells, like ASCs. Therefore this application describes the development of an innovative, new treatment for the repair of cleft palate defects in young children using ASCs. Specifically, this application will: 1) characterize the MAPK pathway in ASC osteogenesis, 2) enhance ASC osteogenesis in vivo through specific manipulation of this pathway, 3) develop a novel, growth-factor free approach promoting ASC-driven bone formation through apatite mediated manipulation of MAPK signaling and 4) determineif these apatite-ASC constructs can form bone in vivo.
One of the most common craniofacial birth defects seen is the cleft palate with one in every 600 newborns being affected in each year in the US. Such defects may be able to be healed in the newborn using a combination of the newborn's own stem cells - derived from their fat - combined with specially designed scaffolds. Such a strategy, if successful, may also have applicability to other common craniofacial abnormalities in children thus decreasing the substantial financial burden imposed each year on the US medical system.
|Tsang, Eric J; Wu, Benjamin; Zuk, Patricia (2018) MAPK signaling has stage-dependent osteogenic effects on human adipose-derived stem cells in vitro. Connect Tissue Res 59:129-146|