A Preview of Selected Articles

Sepsis, the leading cause of death in intensive care units, can occur when an infection prompts a systemic hyper-inflammatory response involving the innate immune system. The accumulation of neutrophils and macrophages and the overproduction of inflammatory cytokines associated with sepsis can cause severe damage to host tissues and organs and prompt multiorgan failure and death. As with many conditions that involve the immune system, mesenchymal stem cells (MSCs) have been proposed as a potential treatment option; in this case, treatment with MSCs aims to dampen the proinflammatory response to inhibit potential tissue/organ damage. However, we still lack a full understanding of how MSCs convey their immunomodulatory function: do paracrine-acting secreted factors mediate this response, thereby creating the possibility of a cell-free therapeutic approach for sepsis, or does any immunomodulation require the presence of MSCs themselves? One of the major consequences of sepsis is the onset of acute kidney injury, with impaired renal function, renal inflammation, microvascular dysfunction, and endothelial cell injury occurring through several different mechanisms. Can MSC therapy also inhibit serious sepsis-associated conditions such as these? In the first of our Featured Articles this month published in STEM CELLS, Weiss et al. employ mouse models of allogeneic heart transplantation and sepsis to highlight the importance of tailoring MSC-based treatments to the disease as opposed to utilizing MSCs as a one-sizefits-all therapeutic solution. In a Related Article published in STEM CELLS Translational Medicine, Cóndor et al. demonstrated that human Wharton's jelly-derived MSCs adequately protected against renal, hepatic, and endothelial dysfunction in a rat model of sepsis. The loss of dopaminergic neurons in the substantia nigra and the subsequent loss of dopamine in the striatum leads to the impaired control of movement observed in patients with Parkinson's disease. Replacement of dopamine can alleviate symptoms; however, we currently lack both effective curative strategies for this debilitating disease and model systems that faithfully recapitulate disease characteristics. The guided differentiation of human pluripotent stem cells (hPSCs) may allow for the development of Parkinson's disease models to screen drugs and evaluate potential therapeutics and for the generation of the dopaminergic neurons required for cell replacement therapies. Unfortunately, attempts to model Parkinson's disease employing hPSCs cultured under conventional two-dimensional conditions have not met with great success; however, recent advances in three-dimensional organoid technology may provide a better approach. Of additional importance, questions remain as to the optimal cell type for cell replacement therapies in Parkinson's disease: are we better to transplant mature dopaminergic neurons, or may stem/ progenitor cells or immature neurons afford the optimal recovery of function? In the second of our Featured Articles this month published in STEM CELLS, Kwak et al. describe a novel method for the generation of homogenous hPSC-derived midbrain-like organoids that may prove useful for the in vitro modeling of Parkinson's disease. In a Related Article published in STEM CELLS Translational Medicine, Qiu et al. reported that transplantation of immature midbrain dopaminergic neurons derived from hPSCs prompted enhanced functional recovery in a Parkinson's disease mouse model when compared with mature neurons and progenitor cells.