Because stem cells are often found to improve repair tissue including heart without evidence of engraftment or differentiation, mechanisms underlying wound healing are still elusive. Several studies have reported that stem cells can fuse with cardiomyocytes either by permanent or partial cell fusion processes. However, the respective physiological impact of these two processes remains unknown in part because of the lack of knowledge of the resulting hybrid cells. To further characterize cell fusion, we cocultured mouse fully differentiated cardiomyocytes with human multipotent adipose-derived stem (hMADS) cells as a model of adult stem cells. We found that heterologous cell fusion promoted cardiomyocyte reprogramming back to a progenitor-like state. The resulting hybrid cells expressed early cardiac commitment and proliferation markers such as GATA-4, myocyte enhancer factor 2C, Nkx2.5, and Ki67 and exhibited a mouse genotype. Interestingly, human bone marrow-derived stem cells shared similar reprogramming properties than hMADS cells but not human fibroblasts, which suggests that these features might be common to multipotent cells. Furthermore, cardiac hybrid cells were preferentially generated by partial rather than permanent cell fusion and that intercellular structures composed of f-actin and microtubule filaments were involved in the process. Finally, we showed that stem cell mitochondria were transferred into cardiomyocytes, persisted in hybrids and were required for somatic cell reprogramming. In conclusion, by providing new insights into previously reported cell fusion processes, our data might contribute to a better understanding of stem cell-mediated regenerative mechanisms and thus, the development of more efficient stem cell-based heart therapies.

Peripheral serotonin, synthesized by tryptophan hydroxylase-1 (TPH ₁ ), has been shown to play a key role in several physiological functions. Recently, controversy has emerged about whether peripheral serotonin has any effect on bone density and remodeling.We therefore decided to investigate in detail bone remodeling in growing and mature TPH ₁ knockout mice (TPH ₁ ^−/− ). Bone resorption in TPH ₁ ^−/− mice, as assessed by biochemical markers and bone histomorphometry, was markedly decreased at both ages. Using bone marrow transplantation, we present evidence that the decrease in bone resorption in TPH ₁ ^−/− mice is cell-autonomous. Cultures from TPH ₁ ^−/− in the presence of macrophage colony-stimulating factor and receptor activator for NF-KB ligand (RANKL) displayed fewer osteoclasts, and the decreased differentiation could be rescued by adding serotonin. Our data also provide evidence that in the presence of RANKL, osteoclast precursors express TPH ₁ and synthesize serotonin. Furthermore, pharmacological inhibition of serotonin receptor 1B with SB224289, and of receptor 2A with ketanserin, also reduced the number of osteoclasts. Our findings reveal that serotonin has an important local action in bone, as it can amplify the effect of RANKL on osteoclastogenesis.

Bidirectional transcription, leading to the expression of an antisense (AS) RNA partially complementary to the protein coding sense (S) RNA, is an emerging subject in mammals and has been associated with various processes such as RNA interference, imprinting and transcription inhibition. Homeobox genes do not escape this bidirectional transcription, raising the possibility that such AS transcription occurs during embryonic development and may be involved in the complexity of regulation of homeobox gene expression. According to the importance of the Msx1 homeobox gene function in craniofacial development, especially in tooth development, the expression and regulation of its recently identified AS transcripts were investigated in vivo in mouse from E9.5 embryo to newborn, and compared with the S transcript and the encoded protein expression pattern and regulation. The spatial and temporal expression patterns of S, AS transcripts and protein are consistent with a role of AS RNA in the regulation of Msx1 expression in timely controlled developmental sites. Epithelial-mesenchymal interactions were shown to control the spatial organization of S and also AS RNA expression during early patterning of incisors and molars in the odontogenic mesenchyme. To conclude, this study clearly identifies the Msx1 AS RNA involvement during tooth development and evidences a new degree of complexity in craniofacial developmental biology: the implication of endogenous AS RNAs.

Objective. To review cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) occurring in association with benign disease and to describe and compare the clinical course and outcome for patients with BRONJ and rheumatoid arthritis (RA) or osteoporosis. Methods. We retrospectively reviewed observations of all patients referred for treatment and followup for BRONJ from January 2007 to December 2011. Only patients with malignant disease were excluded. Demographic data, medical history, maxillofacial findings, BRONJ treatment, and followup were reviewed for each case. Results. Over a 5-year period, we diagnosed 112 patients with BRONJ. Among these patients, 15 received bisphosphonate (BP) treatment for nonmalignant disease (mean age 65.7 ± 19.8 yrs, 80% women). Patients received BP for a variety of reasons: 8 (53%) to prevent osteoporosis in association with underlying RA; 6 (40%) to prevent idiopathic osteoporosis; and 1 (7%) to treat ankle algodystrophy. The mean oral BP exposure period was 48.4 months (median 36 mo). In 13 cases (86.6%), BRONJ was diagnosed following dental extraction. Of the 8 patients with RA, 5 (62.5%) were taking prednisone at the time of the discovery of BRONJ. Major surgery, sequestrectomy, or alveolectomy was performed in 9 patients (60%), all of whom healed within 3 to 36 months (mean 11.5 mo). Comparative analysis of all the variables showed no statistically significant differences between patients with RA and others. Conclusion. ONJ is a rare adverse effect of BP therapy, especially when administered orally. Within the limits of our study, we were unable to demonstrate a difference in BRONJ disease spectrum, clinical course, or outcome between patients with and those without RA.