Mesenchymal stem cells (MSCs) hold great potential for regenerative medicine and tissue-engineering applications. They have multipotent differentiation capabilities and have been shown to differentiate down various lineages, including osteoblasts, adipocytes, chondrocytes, myocytes, and possibly neurons. The majority of approaches to control the MSC fate have been via the use of chemical factors in the form of growth factors within the culture medium. More recently, it has been understood that mechanical forces play a significant role in regulating MSC fate. We and others have shown that mechanical stimuli can control MSC lineage specification. The cytoskeleton is known to play a large role in mechanotransduction, and a growing number of studies are showing that it can also contribute to MSC differentiation. This review analyzes the significant contribution of actin and integrin distribution, and the smaller role of microtubules, in regulating MSC fate. Osteogenic differentiation is more prevalent in MSCs with a stiff, spread actin cytoskeleton and greater numbers of focal adhesions. Both adipogenic differentiation and chondrogenic differentiation are encouraged when MSCs have a spherical morphology associated with a dispersed actin cytoskeleton with few focal adhesions. Different mechanical stimuli can be implemented to alter these cytoskeletal patterns and encourage MSC differentiation to the desired lineage.

The ability of bone-marrow-derived mesenchymal stem cells (MSCs) and adipose-derived stem cells (ASCs) to undergo chondrogenic differentiation has been studied extensively, and it has been suggested that the chondrogenic potential of these stem cells differ from each other. Here, we provide a comprehensive review and analysis of the various growth factor induction agents for MSC and ASC three-dimensional in vitro chondrogenic differentiation. In general, the most common growth factors for chondrogenic induction come from the transforming growth factor beta (TGFbeta) superfamily. To date, the most promising growth factors for chondrogenesis appear to be TGFbeta-3 and bone morphogenetic protein (BMP)-6. A thorough review of the literature indicates that human MSCs (hMSCs) appear to exhibit the highest chondrogenic potential in three-dimensional culture in the medium containing both dexamethasone and TGFbeta-3. Some reports indicate that the addition of BMP-6 to TFGbeta-3 and dexamethasone further increases hMSC chondrogenesis, but these results are still not consistently supported. Induction of human ASC (hASC) chondrogenesis appears most successful when dexamethasone, TGFbeta-3, and BMP-6 are used in combination. However, to date, current formulations do not always result in stable differentiation to the chondrocytic lineage by hMSCs and hASCs. Continued research must be performed to examine the expression cascades of the TFGbeta superfamily to further determine the effects of each growth factor alone and in combination on these stem cell lines.

Skeletal muscle tissue has an inherent capacity for regeneration following injury. However, severe trauma, such as volumetric muscle loss, overwhelms these natural muscle repair mechanisms prompting the search for a tissue engineering/regenerative medicine approach to promote functional skeletal muscle restoration. A desirable approach involves a bioscaffold that simultaneously acts as an inductive microenvironment and as a cell/drug delivery vehicle to encourage muscle ingrowth. Both biologically active, naturally derived materials (such as extracellular matrix) and carefully engineered synthetic polymers have been developed to provide such a muscle regenerative environment. Next generation naturally derived/synthetic “hybrid materials” would combine the advantageous properties of these materials to create an optimal platform for cell/drug delivery and possess inherent bioactive properties. Advances in scaffolds using muscle tissue engineering are reviewed herein.