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In spite of decades of research, no feasible method for obtaining sufficient numbers of uncommitted muscle stem cells (MuSCs) for therapy of degenerative muscle diseases exists. One of the most fundamental problems associated with stem cell therapy of muscle is that removal of MuSCs from their tissue microenvironment and expansion in conventional culture induces their terminal commitment to myogenic differentiation. This in-vitro loss of stemness impairs the long-term engraftment potential of MuSCs and renders them unsuitable for stem cell therapy. In another disease relevant context, aging, dramatic changes in the functionality of MuSCs have been shown to depend on an altered composition of their microenvironment. Thus, muscle progenitors are fundamentally dependent on their local environment, commonly known as the âstem cell niche", and a better understanding of its role in guiding stem cell function is highly relevant for the development of therapies for aging and muscle diseases. The muscle stem cell niche is composed of diverse cellular and acellular elements, including different supportive cell types, growth factors and extracellular matrix, and as outlined above, is critical for maintaining healthy stem cell characteristics such as the capacity for self-renewal, commitment, and differentiation. Using molecular biology approaches, we decided to interrogate (I) the role of the cellular environment on stem cell commitment, (II) to test whether, in a physiological context, the systemic circulation has niche-independent effects on MuSC stemness, and (III) to study a population of MuSC-supportive cells that is affected by the aging process. In the first study of this thesis, we have successfully developed an organoid-like-approach for the scalable derivation of uncommitted MuSCs from human induced pluripotent stem cells (iPSCs) in a biologically faithful cellular 3D-environment in suspension embryoids. To this end, we employed human iPSCs and a spectrum of immortalized cell lines to screen for 3D-aggregation conditions promoting mesoderm formation and subsequent specification to the myogenic lineage without the parallel upregulation of myogenic commitment markers. Compared to myogenic cells derived from adult human skeletal muscle, this niche-mimetic embryoid derived progenitors display significantly enhanced engraftment into the muscle stem cell position peripheral to muscle fibers, and restoration of dystrophin expression when transplanted into muscles of a mouse model of Duchenne muscular dystrophy. In a second study, we present a novel method for encapsulation of human muscle progenitors in highly diffusible polyethersulfone hollow fiber capsules to identify highly specific "transcriptional-signature" induced by systemic aging in-vivo. This technique allows to study the systemic circulation in health, disease and aging at an unprecedented level in human cell types of choice. Finally, in our third study, we investigated the cellular cross-talk between muscle stem cells and non-myogenic niche-based cell type, called fibro/adipogenic progenitors (FAPs). Interestingly, the support-function and the cross-talk with stem cells are dramatically impaired in aged FAPs. We demonstrate that this mechanism can be targeted to rejuvenate myogenesis. Taken together, "mimicking" the physicochemical-interactions of MuSCs with their niche-resident cell types, represents a powerful opportunity to manipulate MuSC function in aging and disease.