A Preview of Selected Articles

Patients carrying point mutations in the β-globin gene suffer from sickle cell disease, a condition in which the mutant globin protein produced promotes red blood cell deformation into a sickle or crescent shape under stress-inducing conditions. This deformation can induce premature death of red blood cells or the blockage of small blood vessels, leading to symptoms that can range from hemolytic anemia to multiorgan damage and early mortality. The synergism of patient-derived induced pluripotent stem cell (iPSC) generation, gene editing via zinc finger nucleases, transcription activator-like effector nucleases, and CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9, and directed hematopoietic differentiation aims to provide an alternative source of both corrected red blood cells/platelets for transfusion and hematopoietic stem/ progenitor cells for transplantation. How far have we advanced toward reaching this lofty aim in the realm of sickle cell disease? And can we apply what we currently understand to other related diseases? In the first of our Featured Articles published this month in STEM CELLS Translational Medicine, Haro-Mora et al describe both the gene correction of a sickle cell disease mutation in patient-derived iPSCs and their differentiation into corrected erythrocytes employing a feederand serum-free methodology and the generation of a hemangioblast-like structure containing hematopoietic-like spherical cells. In a Related Article published recently in STEM CELLS, Huang et al. employed CRISPR/ Cas9-mediated gene editing to correct a sickle cell disease mutation in patient-derived iPSCs and permit the production of erythrocytes expressing the appropriate globin protein from the corrected allele. Autophagy, a catabolic protein degradation and recycling pathway that ensures cellular homeostasis and proper function, removes unnecessary or dysfunctional cellular components through the generation and activity of double-membrane vesicles called autophagosomes that engulf cellular proteins and organelles for delivery to the lysosome. Interestingly, studies into the role of autophagy in disease, including cancer, inflammatory bowel disease, and neurodegeneration, have established that autophagy can promote both cell survival and cell death in a context-specific manner. In contrast, a general reduction in autophagy accompanies the normal aging process. Overall, an extensive research base has provided evidence that the targeted modulation of autophagic activity may represent an exciting means to improve therapeutic outcomes in multiple conditions. In the realm of stem cells, autophagic function appears to balance quiescence, selfrenewal, and differentiation under normal physiological and stressinducing conditions; therefore, can the modulation of autophagy in stem cells also foster enhanced regenerative outcomes? In the second of our Featured Articles published this month in STEM CELLS Translational Medicine, Zhu et al demonstrate that the administration of engineered neural stem cells (NSCs) can decrease autophagy, reverse the hypoxic microenvironment, and reduce central nervous system glial scar formation to permit improvements to locomotor function following spinal cord injury. In a Related Article published recently in STEM CELLS, Matsumoto et al described how a signaling cascade involving autophagy, short telomeres, and p53 regulates the age-associated detrimental changes in the cell fate of cardiac stem/ progenitor cells (CPCs) and identified a means to rejuvenate aged CPCs and improve cardiac therapy.