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Skeletal muscle is susceptible to injury following trauma, neurological dysfunction, and genetic diseases. Skeletal muscle homeostasis is maintained by a pronounced regenerative capacity, which includes the recruitment of stem cells. Chronic exposure to tumor necrosis factor-␣ (TNF) triggers a muscle wasting reminiscent of cachexia. To better understand the effects of TNF upon muscle homeostasis and stem cells, we exposed injured muscle to TNF at specific time points during regeneration. TNF exposure delayed the appearance of regenerating fibers, without exacerbating fiber death following the initial trauma. We observed modest cellular caspase activation during regeneration, which was markedly increased in response to TNF exposure concomitant with an inhibition in regeneration. Caspase activation did not lead to apoptosis and did not involve caspase-3. Inhibition of caspase activity improved muscle regeneration in either the absence or the presence of TNF, revealing a nonapoptotic role for this pathway in the myogenic program. Caspase activity was localized to the interstitial cells, which also express Sca-1, CD34, and PW1. Perturbation of PW1 activity blocked caspase activation and improved regeneration. The restricted localization of Sca-1؉ cells to a subset of interstitial cells with caspase activity reveals a critical regulatory role for this population during myogenesis, which may directly contribute to resident muscle stem cells or indirectly regulate stem cells through cell-cell interactions. STEM CELLS 2008;26: 997-1008 Disclosure of potential conflicts of interest is found at the end of this article.

Background: Epidemiologic data revealed increased brain tumor incidence in workers exposed to magnetic fields (MFs), raising concerns about the possible link between MF exposure and cancer. However, MFs seem to be neither mutagenic nor tumorigenic. The mechanism of their tumorigenic effect has not been elucidated. Methods: To evaluate the interference of MFs with physical (heat shock, HS) and chemical (etoposide, VP16) induced apoptoses, respectively, we exposed a human glioblastoma primary culture to 6 mT static MF. We investigated cytosolic Ca 2ϩ ([Ca 2ϩ ] i ) fluxes and extent of apoptosis as key endpoints. The effect of MFs on HS-and VP16-induced apoptoses in primary glioblastoma cultures from four patients was also tested. Results: Static MFs increased the [Ca 2ϩ ] i from a basal value of 124 Ϯ 4 nM to 233 Ϯ 43 nM (P Ͻ 0.05). MF exposure dramatically reduced the extent of HS-and

Tissue engineering (TE) for tissue and organ regeneration or replacement is generally performed with scaffold implants, which provide structural and molecular support to in vitro seeded or in vivo recruited cells. TE implants elicit the host immune response, often resulting in engraftment impediment or rejection. Besides this negative effect, however, the immune system components also yield a positive influence on stem cell recruitment and differentiation, allowing tissue regeneration and healing. Thus, a balanced cooperation between proinflammatory and proresolution players of the immune response is an essential element of implant success. In this context, macrophage plasticity plays a fundamental role. Therefore modulating the immune response, instead of immune suppressing the host, might be the best way to successfully implant TE tissues or organs. In particular, it is becoming evident that the scaffold, immune, and stem cells are linked by a three-way interaction, and many efforts are being made for scaffold-appropriate design and functionalization in order to drive the inflammation process toward regeneration, vascularization, and implant success. This review discusses current and potential strategies for inflammation modulation to aid engraftment and regeneration, supporting the concept that quality, and not quantity, of inflammation might influence implant success.Keywords: Implant r Macrophage r Scaffold r Stem cell r Tissue engineering IntroductionTissue engineering and regenerative medicine (TERM) applications intend to improve or replace compromised biological functions by stimulating the intrinsic regenerative capacity of the body or even by replacing damaged tissues and organs. To provide the structure and attachment surface to drive tissue regeneration, Correspondence: Prof. Laura Teodori e-mail: laura.teodori@enea.it scaffolds of synthetic, or natural origin, which may or may not be seeded with stem cells, are constructed and implanted into the human body to foster regeneration. Scaffolds are particularly important for the replacement of a variety of tissues such as skin, bone, and muscle tissue (e.g. maxillofacial reconstructions, heart valves, and vessels) [1]. Depending on the type of tissue to be * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 3222-3236 HIGHLIGHTS 3223replaced, different types of scaffolds are suitable to support regeneration and engraftment. This review provides a general view on the different biomaterials/scaffold types and properties; however the available literature on the matter extensively reports the most frequently used types of scaffolds and their application [2,3]. Although TERM research greatly advanced in recent years, one major challenge is the immune response elicited by the implant, which often leads to a precocious reabsorption, to fibrosis of the implant, and/or to implant rejection, leading to eventual failure of the intervention [4]. To ensure the success of t...