Interplay of Nkx3.2, Sox9 and Pax3 Regulates Chondrogenic Differentiation of Muscle Progenitor Cells

Muscle satellite cells make up a stem cell population that is capable of differentiating into myocytes and contributing to muscle regeneration upon injury. In this work we investigate the mechanism by which these muscle progenitor cells adopt an alternative cell fate, the cartilage fate. We show that chick muscle satellite cells that normally would undergo myogenesis can be converted to express cartilage matrix proteins in vitro when cultured in chondrogenic medium containing TGFß3 or BMP2. In the meantime, the myogenic program is repressed, suggesting that muscle satellite cells have undergone chondrogenic differentiation. Furthermore, ectopic expression of the myogenic factor Pax3 prevents chondrogenesis in these cells, while chondrogenic factors Nkx3.2 and Sox9 act downstream of TGFß or BMP2 to promote this cell fate transition. We found that Nkx3.2 and Sox9 repress the activity of the Pax3 promoter and that Nkx3.2 acts as a transcriptional repressor in this process. Importantly, a reverse function mutant of Nkx3.2 blocks the ability of Sox9 to both inhibit myogenesis and induce chondrogenesis, suggesting that Nkx3.2 is required for Sox9 to promote chondrogenic differentiation in satellite cells. Finally, we found that in an in vivo mouse model of fracture healing where muscle progenitor cells were lineage-traced, Nkx3.2 and Sox9 are significantly upregulated while Pax3 is significantly downregulated in the muscle progenitor cells that give rise to chondrocytes during fracture repair. Thus our in vitro and in vivo analyses suggest that the balance of Pax3, Nkx3.2 and Sox9 may act as a molecular switch during the chondrogenic differentiation of muscle progenitor cells, which may be important for fracture healing

Classical humanitarianism and resilience humanitarianism: making sense of two brands of humanitarian action

Abstract Humanitarian aid has long been dominated by a classical, Dunantist paradigm that was based on the ethics of the humanitarian principles and centred on international humanitarian United Nations agencies and non-governmental organizations. While in previous decades alternative paradigms and humanitarianisms evolved, this classical paradigm remained the central narrative of humanitarianism. In recent years, however, this paradigm has been paralleled by a resilience paradigm that is focused on local people and institutions as the first responders to crises. Whereas classical humanitarianism is rooted in the notion of exceptionalism, resilience humanitarianism starts from the idea of crisis as the new normality. This paper discusses the two paradigms and the incongruent images they evoke about crises, local institutions and the recipients of aid. The article puts forward the case for studying the ways in which these contrasting aid paradigms shape practices, dealing with the importance of discourse, the social life of policy, the multiplicity of interests, the power relations and the crucial importance of understanding the lifeworld and agency of aid workers and crisis-affected communities. The article demonstrates how the stories that humanitarians tell about themselves are based on highly selective views of reality and do not include the role they themselves play in the reordering and representation of realities in humanitarian crises