Scars are a consequence of cutaneous wound healing that can be both unsightly and detrimental to the function of the tissue. Scar tissue is generated by excessive deposition of extracellular matrix tissue by wound healing fibroblasts and myofibroblasts, and although it is inferior to the uninjured skin, it is able to restore integrity to the boundary between the body and its environment. Scarring is not a necessary process to repair the dermal tissues. Rather, scar tissue forms due to specific mechanisms that occur during the adult wound healing process and are modulated primarily by the inflammatory response at the site of injury. Adult tissue-derived mesenchymal stem cells, which participate in normal wound healing, are trophic mediators of tissue repair. These cells participate in attenuating inflammation in the wound and reprogramming the resident immune and wound healing cells to favor tissue regeneration and inhibit fibrotic tissue formation. As a result, these cells have been considered and tested as a likely candidate for a cellular therapy to promote scar-less wound healing. This review identifies specific mechanisms by which mesenchymal stem cells can limit tissue fibrosis and summarizes recent in vivo studies where these cells have been used successfully to limit scar formation.

There is enormous worldwide demand for therapies to promote the efficient resolution of hard-to-heal wounds with minimal appearance of scarring. Recent in vitro studies with mesenchymal stem cells (MSCs) have identified numerous mechanisms by which these cells can promote the process of wound healing, and there is significant interest in the clinical translation of an MSC-based therapy to promote dermal regeneration. This review provides a systematic analysis of recent preclinical and clinical research to evaluate the use of MSCs in wound healing applications. These in vivo studies provide overwhelming evidence that MSCs can accelerate wound closure by modulating the inflammatory environment, promoting the formation of a well-vascularized granulation matrix, encouraging the migration of keratinocytes, and inhibiting apoptosis of wound healing cells. The trophic effects of MSC therapy also appear to augment wound healing in diabetic tissues, thereby preventing the formation of nonhealing ulcers. Finally, a number of delivery systems have been evaluated and indicate that MSCs could be the basis of a versatile therapy to fulfill the clinical needs for dermal regeneration. However, despite the apparent advantages of MSC-based therapies, there have been only limited clinical investigations of this type of therapy in humans. Thus, our review concludes with a discussion of the translational barriers that are limiting the widespread clinical use of MSCs to enhance wound healing.

This review focuses on current tissue engineering strategies for promoting vascularized bone regeneration. We review the role of angiogenic growth factors in promoting vascularized bone regeneration and discuss the different therapeutic strategies for controlled/sustained growth factor delivery. Next, we address the therapeutic uses of stem cells in vascularized bone regeneration. Specifically, this review addresses the concept of co-culture using osteogenic and vasculogenic stem cells, and how adipose derived stem cells compare to bone marrow derived mesenchymal stem cells in the promotion of angiogenesis. We conclude this review with a discussion of a novel approach to bone regeneration through a cartilage intermediate, and discuss why it has the potential to be more effective than traditional bone grafting methods.

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Degeneration of the intevertebral disc represents a significant musculoskeletal disease burden. Although spinal fusion has some efficacy in pain management, spine biomechanics is ultimately compromised. In addition, there is inherent limitation of hardware-based IVD replacement prostheses, which underscores the importance of biological approaches to disc repair. In this study, we have seeded multipotent, adult human mesenchymal stem cells (MSCs) into a novel biomaterial amalgam to develop a biphasic construct that consisted of electrospun, biodegradable nanofiber scaffold (NFS) enveloping a hyaluronic acid (HA) hydrogel center. The seeded MSCs were induced to undergo chondrogenesis in vitro in the presence of transforming growth factor-β for up to 28 days. The cartilaginous HANFS construct architecturally resembled a native intervertebral disc, with an outer annulus fibrosus (AF)-like region and inner nucleus pulposus (NP)-like region. Histological and biochemical analyses, immunohistochemistry, and gene expression profiling revealed the time-dependent development of chondrocytic phenotype of the seeded cells. Taken together, these findings suggest the prototypic potential of MSC-seeded HANFS constructs for the tissue engineering of biological replacements of degenerated IVD.

We have generated a bioinspired tunable system of hyaluronic acid (HyA)-based hydrogels for Matrix-Assisted Cell Transplantation (MACT). With this material, we have independently evaluated matrix parameters such as adhesion peptide density, mechanical properties, and growth factor sequestering capacity, to engineer an environment that imbues donor cells with a milieu that promotes survival and engraftment with host tissues after transplantation. Using a versatile population of Sca-1+/CD45− cardiac progenitor cells (CPCs), we demonstrated that the addition of heparin in the HyA hydrogels was necessary to coordinate the presentation of TGFβ1 and to support the trophic functions of the CPCs via endothelial cell differentiation and vascular like tubular network formation. Presentation of exogenous TGFβ1 by binding with heparin improved differentiated CPC function by sequestering additional endogenously-produced angiogenic factors. Finally, we demonstrated that TGFβ1 and heparin-containing HyA hydrogels can promote CPC survival when implanted subcutaneously into murine hind-limbs and encouraged their participation in the ensuing neovascular response, including blood vessels that had anastomosed with the host’s blood vessels.

Importance of the field-Mesenchymal adult stem cells have properties that make them attractive for use in tissue engineering and regenerative medicine. They are inherently plastic, enabling them to differentiate along different lineages, and promote wound healing and regeneration of surrounding tissues by modulating immune and inflammatory responses, promoting angiogenesis and secreting other trophic factors. Unlike embryonic stem cells, clinical uses of mesenchymal stem cells are not encumbered by ethical considerations or legal restrictions.Areas covered in this review-We discuss skeletal muscle as a source of mesenchymal stem and progenitor cells by reviewing their biology and current applications in tissue engineering and regenerative medicine. This paper covers literature from the last 5 -10 years.What the reader will gain-Skeletal muscle is a plentiful source of mesenchymal stem and progenitor cells. This tissue may be obtained via routine biopsy or collection after surgical debridement. We describe the biology of these cells and provide an overview of therapeutic applications currently being developed to take advantage of their regenerative properties.Take home message-There is potential for stem and progenitor cells derived from skeletal muscle to be incorporated in clinical interventions, either as a cellular therapy to modify the natural history of disease or as a component of engineered tissue constructs that can replace diseased or damaged tissues.

Mesenchymal stem cells (MSCs) are attractive candidates for inclusion in cell-based therapies by virtue of their abilities to home to wound sites. However, in-depth characterization of the specific effects of MSCs on their microenvironments is needed to realize their full therapeutic potentials. Furthermore, since MSCs of varying properties can be isolated from a diverse spectrum of tissues, a strategic and rational approach in MSC sourcing for a particular application has yet to be achieved. For example, MSCs that activate their proteolytic environments may promote tissue remodeling, while those from different tissue sources may inhibit proteases and promote tissue stabilization. This study attempts to address these issues by analyzing MSCs isolated from three adult tissue sources in terms of their effects on their proteolytic microenvironments. Human bone marrow, adipose, and traumatized muscle derived MSCs were compared in their soluble and cellular-associated MMP components and activity. For all types of MSCs, MMP activity associated with the cell surface, but activity levels and MMP profiles differed with tissue source. All MSC types bound exogenous active MMPs at their surfaces. MSCs were also able to activate exogenous proMMP-2 and proMMP-13. This is in marked contrast to the MSC soluble compartment, which strongly inhibited MMPs via endogenous TIMPs. The exact TIMP used to inhibit the exogenous MMP differed with MSC type. Thus, MSCs saturate their environment with both MMPs and TIMPs. Since they bind and activate MMPs at their surfaces, the net result is a very controlled pericellular localization of MMP activities by MSCs.