All multicellular organisms rely on intercellular communication networks to coordinate physiological functions. As members of a dynamic social network, each cell receives, processes, and redistributes biological information to define and maintain tissue homeostasis. Uncovering the molecular programs underlying these processes is critical for prevention of disease and aging and development of therapeutics. The study of intercellular communication requires techniques that reduce the scale and complexity of in vivo biological networks while resolving the molecular heterogeneity in “omic” layers that contribute to cell state and function. Recent advances in microengineering and high‐throughput genomics offer unprecedented spatiotemporal control over cellular interactions and the ability to study intercellular communication in a high‐throughput and mechanistic manner. Herein, this review discusses how salient engineered approaches and sequencing techniques can be applied to understand collective cell behavior and tissue functions.
Significance Skeletal muscle is one of the largest tissues in the body and can regenerate when damaged through a population of resident muscle stem cells. A type of muscle trauma called volumetric muscle loss overwhelms the regenerative capacity of muscle stem cells and engenders fibrotic supplantation. A comparison of muscle injuries resulting in regeneration or fibrosis revealed that intercellular communication between neutrophils and natural killer cells impacts muscle stem cell-mediated repair. Perturbation of neutrophil–natural killer cell interactions resulted in a variation of healing outcomes and suggested that immunomodulatory interventions can be effective to prevent aberrant healing outcomes.
During aging and neuromuscular diseases, there is a progressive loss of skeletal muscle volume and function impacting mobility and quality of life. Muscle loss is often associated with denervation and a loss of resident muscle stem cells (satellite cells or MuSCs), however, the relationship between MuSCs and innervation has not been established. Herein, we administered severe neuromuscular trauma to a transgenic murine model that permits MuSC lineage tracing. We show that a subset of MuSCs specifically engraft in a position proximal to the neuromuscular junction (NMJ), the synapse between myofibers and motor neurons, in healthy young adult muscles. In aging and in a mouse model of neuromuscular degeneration (Cu/Zn superoxide dismutase knockout – Sod1-/-), this localized engraftment behavior was reduced. Genetic rescue of motor neurons in Sod1-/- mice reestablished integrity of the NMJ in a manner akin to young muscle and partially restored MuSC ability to engraft into positions proximal to the NMJ. Using single cell RNA-sequencing of MuSCs isolated from aged muscle, we demonstrate that a subset of MuSCs are molecularly distinguishable from MuSCs responding to myofiber injury and share similarity to synaptic myonuclei. Collectively, these data reveal unique features of MuSCs that respond to synaptic perturbations caused by aging and other stressors.
Tumor necrosis factor-alpha (TNF-alpha) has been found to be elevated in patients during hemodialysis and is thought to mediate some of the immune and metabolic dysfunctions in these patients. It has been speculated that infusions of soluble TNF receptor (sTNF-R) may prevent some of the cytotoxic effects of TNF. However, little is still known about preexisting serum TNF-R levels in patients with chronic renal failure, with or without hemodialysis. Therefore we analyzed serum samples of sTNF-R in 26 patients with chronic renal failure (group I), 61 hemodialysis patients (group II), 9 renal transplant recipients with acute renal failure requiring posttransplant dialysis (group III), 13 renal transplant patients with rejection and moderate kidney dysfunction (group IV), and 21 renal transplant recipients with borderline kidney dysfunction and diverse infectious complications (group V). Control groups consisted of 34 blood donors and diseased controls (11 renal transplant recipients with normal kidney function without complications). All patient groups showed significantly higher sTNF-R levels compared to the control groups. In groups I, IV, and V comparable levels were observed. In group I there was a clear correlation between sTNF-R levels and serum creatinine. The highest sTNF-R serum levels were seen in groups II and III, but there was no correlation with creatinine. In the posttransplant cases (group III and diseased controls) there was a decrease in sTNF-R with improvement of kidney function. These data strongly suggest that sTNF-R serum levels are dependent on kidney function.
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