Bentzinger Lab
Skeletal Muscle Stem Cells
Somatic stem cells allow for repair and maintenance of tissues throughout the lifetime of an organism. Self-renewal enables these stem cells to persist in an uncommitted state while supplying progeny for differentiation. In skeletal muscle this function is governed by muscle stem cells (MuSCs), also known as “satellite cells”. Under homeostatic conditions in adult muscle tissue, MuSCs are localized in between the extracellular matrix (ECM) surrounding muscle fibers and the muscle fiber plasma membrane in a quiescent state. When activated by stimuli such as muscle injury or exercise, MuSCs will rapidly enter mitosis. Following this proliferative response a subset of MuSCs differentiates and fuses to form new syncytial muscle fibers or to repair damaged existing fibers. Once tissue repair is complete the MuSC pool will return to quiescence. Owing to the MuSCs, muscle tissue has an outstanding regenerative capacity allowing it to go through multiple rounds of injury and repair without any functional impairment. Over the last decade muscle tissue has become one of the most studied model systems in the field of adult stem cell biology. The abundance and relative accessibility of skeletal muscle allows for a range of elaborate experimental techniques for the study of its stem cells and a variety of markers for their identification and isolation have been established.
ECM Regulation of MuSCs
Apart from intrinsic regulatory mechanisms, the stem cell characteristics of MuSCs are critically dependent on their microenvironment. Our lab is interested in understanding the cellular and acellular elements in the niche regulate MuSCs. A major focus of our work is to study the function and composition of the extracellular matrix in regulating MuSCs under homeostatic conditions and following muscle injury. Our previous work has shown that committed MuSCs generated through asymmetric division feed-back to maintain the stem cell character of their mother-cell by providing ECM cues (Bentzinger et al. Cell Stem Cell, 2013). Moreover, similar ECM components are released in bulk into regenerating muscle tissue by a population of cells positive for lineage markers of the hematopoietic system (Lukjanenko et al. Nature Medicine, 2016). Adherence of MuSCs to this transient matrix is required to prevent anchorage dependent cell death (anoikis). Our current research focuses on the role of ECM components involved in maintaining the quiescent state of MuSCs and how these mechanisms are perturbed in disease.
Cellular Dynamics in the MuSC Niche
Depending on the stage of muscle repair following injury or exercise the MuSC niche contains a multitude of different regulatory cell types. We are interested in understanding how these cell populations are coordinated and how they interact with MuSCs. Current work in the group aims at studying a particular support cell type in the niche that conveys systemic signals to MuSCs.
Enhancing Endogenous Repair
The regenerative capacity of skeletal muscle tissue can be severely affected by muscular dystrophies. Most forms of this disease are caused by genetic defects that lead to an instability of muscle fibers. As a consequence, continuous cycles of de- and regeneration cause persistent inflammation. These processes elicit alterations in the niche that inhibit the normal function of MuSCs, for instance through the fibrotic accumulation of ECM molecules. At a certain point in disease progression, MuSCs fail to compensate for the necrotic loss of muscle fibers leading to regenerative failure. Thus, in late stages of the disease muscle function can become severely compromised. Normalization of the pathologic niche and remobilization of the endogenous stem cell pool could help to maintain functional muscles and represents a novel treatment approach for muscular dystrophy (Bentzinger et al., Regenerative Medicine, 2013). We are trying to understand the impact of fibrotic accumulation of ECM on MuSCs to develop strategies for boosting endogenous repair.