Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness

By dividing asymmetrically, stem cells can generate two daughter cells with distinct fates. However, evidence is limited in mammalian systems for the selective apportioning of subcellular contents between daughters. We followed the fates of old and young organelles during the division of human mammary stemlike cells and found that such cells apportion aged mitochondria asymmetrically between daughter cells. Daughter cells that received fewer old mitochondria maintained stem cell traits. Inhibition of mitochondrial fission disrupted both the age-dependent subcellular localization and segregation of mitochondria and caused loss of stem cell properties in the progeny cells. Hence, mechanisms exist for mammalian stemlike cells to asymmetrically sort aged and young mitochondria, and these are important for maintaining stemness properties.National Science Foundation (U.S.). Long-Term Ecological Research Program (DEB-8811884)National Science Foundation (U.S.). Long-Term Ecological Research Program (DEB-9411972)National Science Foundation (U.S.). Long-Term Ecological Research Program (DEB-0080382)National Science Foundation (U.S.). Long-Term Ecological Research Program (DEB-0620652)National Science Foundation (U.S.). Long-Term Ecological Research Program (DEB-1234162)National Science Foundation (U.S.). (Biocomplexity Coupled Biogeocemhical Cycles. DEB-0322057)National Science Foundation (U.S.). Long-Term Research in Environmental Biology (DEB-0716587)National Science Foundation (U.S.). Long-Term Research in Environmental Biology (DEB-1242531)National Science Foundation (U.S.). Long-Term Research in Ecosystem Sciences (DEB-1120064)United States. Dept. of Energy. Program for Ecoysystem Research (DE-FG02-96ER62291)United States. Dept. of Energy. Office of Biological and Environmental Research. National Institute for Climatic Change Research (Grant DE-FC02-06ER64158

Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model

Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children