Focus on Extracellular Vesicles: Therapeutic Potential of Stem Cell-Derived Extracellular Vesicles.

The intense research focus on stem and progenitor cells could be attributed to their differentiation potential to generate new cells to replace diseased or lost cells in many highly intractable degenerative diseases, such as Alzheimer disease, multiple sclerosis, and heart diseases. However, experimental and clinical studies have increasingly attributed the therapeutic efficacy of these cells to their secretion. While stem and progenitor cells secreted many therapeutic molecules, none of these molecules singly or in combination could recapitulate the functional effects of stem cell transplantations. Recently, it was reported that extracellular vesicles (EVs) could recapitulate the therapeutic effects of stem cell transplantation. Based on the observations reported thus far, the prevailing hypothesis is that stem cell EVs exert their therapeutic effects by transferring biologically active molecules such as proteins, lipids, mRNA, and microRNA from the stem cells to injured or diseased cells. In this respect, stem cell EVs are similar to EVs from other cell types. They are both primarily vehicles for intercellular communication. Therefore, the differentiating factor is likely due to the composition of their cargo. The cargo of EVs from different cell types are known to include a common set of proteins and also proteins that reflect the cell source of the EVs and the physiological or pathological state of the cell source. Hence, elucidation of the stem cell EV cargo would provide an insight into the multiple physiological or biochemical changes necessary to affect the many reported stem cell-based therapeutic outcomes in a variety of experimental models and clinical trials.

A tetramethylpyrazine-loaded hyaluronic acid-based hydrogel modulates macrophage polarization for promoting wound recovery in diabetic mice.

The failure of wound healing often causes lower limb disability and amputation of diabetic patients. Current strategies for diabetic wound management often fail to achieve the expected outcomes, and emerging alternatives are urgently needed. Recent advances in the identification of active compounds from traditional herbal medicines provide promising therapeutics for tissue repair and regeneration. In this study, the pro-healing effects of tetramethylpyrazine (TMP, a natural alkaloid found in Ligusticum chuanxiong Hort) for diabetic wounds were for the first time demonstrated. The cutaneous healing was mainly achieved by TMP-mediated macrophage polarization from pro-inflammatory to pro-healing phenotype. In addition, the topical administration of TMP was facilitated by the hyaluronic acid (HA) hydrogel for promoting the full-thickness wounds in the experimental diabetic mice. Consequently, TMP-loaded HA hydrogel (TMP-HA) profoundly accelerated the wound closure in comparison with TMP-loaded INTRASITE Gel (it is a commercial hydrogel), which was evident with the inflammation mitigation, the angiogenesis enhancement, and the collagen deposition. Our work reveals the macrophage-modulatory function of TMP for diabetic wound healing and demonstrates great potential of TMP-HA for clinical application.

Mechanotransduction through adhesion molecules: Emerging roles in regulating the stem cell niche.

Stem cells have been shown to play an important role in regenerative medicine due to their proliferative and differentiation potential. The challenge, however, lies in regulating and controlling their potential for this purpose. Stem cells are regulated by growth factors as well as an array of biochemical and mechanical signals. While the role of biochemical signals and growth factors in regulating stem cell homeostasis is well explored, the role of mechanical signals has only just started to be investigated. Stem cells interact with their niche or to other stem cells via adhesion molecules that eventually transduce mechanical cues to maintain their homeostatic function. Here, we present a comprehensive review on our current understanding of the influence of the forces perceived by cell adhesion molecules on the regulation of stem cells. Additionally, we provide insights on how this deeper understanding of mechanobiology of stem cells has translated toward therapeutics.

In vitro Culture of Naïve Human Bone Marrow Mesenchymal Stem Cells: A Stemness Based Approach.

Human bone marrow derived mesenchymal stem cells (BM-MSCs) resides in their niches in close proximity to hematopoietic stem cells (HSCs). These naïve MSCs have tremendous potential in regenerative therapeutics, and may also be exploited by cancer and infectious disease agents. Hence, it is important to study the physiological and pathological roles of naïve MSC. However, our knowledge of naïve MSCs is limited by lack of appropriate isolation and in vitro culture methods. Established culture methods use serum rich media, and serial passaging for retrospective isolation of MSCs. These primed MSCs may not reflect the true physiological and pathological roles of naive MSCs (Figure 1). Therefore, there is a strong need for direct isolation and in vitro culture of naïve MSCs to study their stemness (self-renewal and undifferentiated state) and developmental ontogeny. We have taken a niche-based approach on stemness to better maintain naïve MSCs in vitro. In this approach, stemness is broadly divided as niche dependent (extrinsic), niche independent (intrinsic) and niche modulatory (altruistic or competitive). Using this approach, we were able to maintain naïve CD271+/CD133+ BM-MSCs for 2 weeks. Furthermore, this in vitro culture system helped us to identify naïve MSCs as a protective niche site for Mycobacterium tuberculosis, the causative organism of pulmonary tuberculosis. In this review, we discuss the in vitro culture of primed vs. naïve human BM derived MSCs with a special focus on how a stemness based approach could facilitate the study of naïve BM-MSCs.

Vascularisation in regenerative therapeutics and surgery.

Vascularisation is often deemed the holy grail of tissue engineering because it is one of the key preconditions that determine the in vivo viability of tissue constructs. Given that a well-developed vascular network allows greater complexity in tissue design and helps regulate tissue metabolism, it appears that the overall outcome of engineered tissue implants depends on the success of microvessel formation, maturation and patterning. Current approaches to vascularising tissue include both in vivo and ex vivo techniques, where blood vessel formation is either spontaneous or guided by physical or biochemical factors. The success of these strategies can then be monitored and evaluated for clinical benefit through numerous standard and novel strategies. Despite the impressive progress in the field of tissue engineering in recent times, there are still numerous technical, immunological, surgical and ethical challenges to overcome. Future prospects in this field are likely to depend on the adoption of a wide-ranging approach incorporating a combination of salient themes such as genetic manipulation, modular assembly and bioreactor coupling. Where applicable, the potential contributions of nanobiotechnology to tissue vascularisation will be discussed as appropriate.