IL-34, the rationale for its expression in physiological and pathological conditions.

IL-34 is a cytokine that shares one of its receptors with CSF-1. It has long been thought that CSF-1 receptor (CSF-1R) receives signals only from CSF-1, but the identification of IL-34 reversed this stereotype. Regardless of low structural homology, IL-34 and CSF-1 emanate similar downstream signaling through binding to CSF-1R and provoke similar but different physiological events afterward. In addition to CSF-1R, protein-tyrosine phosphatase (PTP)-ζ and Syndecan-1 were also identified as IL-34 receptors and shown to be at play. Although IL-34 expression is limited to particular tissues in physiological conditions, previous studies have revealed that it is upregulated in several diseases. In cancer, IL-34 is produced by several types of tumor cells and contributes to therapy resistance and disease progression. A recent study has demonstrated that tumor cell-derived IL-34 abrogates immunotherapy efficacy through myeloid cell remodeling. On the other hand, IL-34 expression is downregulated in some brain and dermal disorders. Despite accumulating insights, our understanding of IL-34 may not be even close to its nature. This review aims to comprehensively describe the physiological and pathological roles of IL-34 based on its similarity and differences to CSF-1 and discuss the rationale for its disease-dependent expression pattern.

Induction of allograft tolerance by adoptive transfer of donor B cells: an immune regulatory strategy for transplantation using MHC-matched iPS cells.

For cellular or tissue transplantation using induced pluripotent stem cells (iPSCs), from the viewpoint of time and economic cost, the use of allogeneic ones is being considered. Immune regulation is one of the key issues in successful allogeneic transplantation. To reduce the risk of rejection, several attempts have been reported to eliminate effects of the major histocompatibility complex (MHC) on the iPSC-derived grafts. On the other hand, we have shown that minor antigen-induced rejection is not negligible even when the MHC's impact is mitigated. In organ transplantation, it is known that donor-specific transfusion (DST) can specifically control immune responses to the donor. However, whether DST could control the immune response in iPSC-based transplantation was not clarified. In this study, using a mouse skin transplantation model, we demonstrate that infusion of donor splenocytes can promote allograft tolerance in the MHC-matched but minor antigen-mismatched conditions. When narrowing down the cell types, we found that infusion of isolated splenic B cells was sufficient to control rejection. As a mechanism, the administration of donor B cells induced unresponsiveness but not deletion in recipient T cells, suggesting that the tolerance was induced in the periphery. The donor B cell transfusion induced allogeneic iPSC engraftment. These results suggest for the first time a possibility that DST using donor B cells could induce tolerance against allogeneic iPSC-derived grafts.

Induced pluripotent stem cell-derived hematopoietic stem and progenitor cells induce mixed chimerism and donor-specific allograft tolerance.

In transplantation using allogeneic induced pluripotent stem cells (iPSCs), strategies focused on major histocompatibility complexes were adopted to avoid immune rejection. We showed that minor antigen mismatches are a risk factor for graft rejection, indicating that immune regulation remains one of the most important issues. In organ transplantation, it has been known that mixed chimerism using donor-derived hematopoietic stem/progenitor cells (HSPCs) can induce donor-specific tolerance. However, it is unclear whether iPSC-derived HSPCs (iHSPCs) can induce allograft tolerance. We showed that 2 hematopoietic transcription factors, Hoxb4 and Lhx2, can efficiently expand iHSPCs with a c-Kit+Sca-1+Lineage- phenotype, which possesses long-term hematopoietic repopulating potential. We also demonstrated that these iHSPCs can form hematopoietic chimeras in allogeneic recipients and induce allograft tolerance in murine skin and iPSC transplantation. With mechanistic analyses, both central and peripheral mechanisms were suggested. We demonstrated the basic concept of tolerance induction using iHSPCs in allogeneic iPSC-based transplantation.

Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of therapeutic targets. The paucity of effective treatment options motivated a number of studies to tackle this problem. Immunosuppressive cells infiltrated into the tumor microenvironment (TME) of TNBC are currently considered as candidates for new therapeutic targets. Myeloid-derived suppressor cells (MDSCs) have been reported to populate in the TME of TNBC, but their roles in the clinical and biological features of TNBC have not been clarified. This study identified that interleukin-34 (IL-34) released by TNBC cells is a crucial immunomodulator to regulate MDSCs accumulation in the TME. We provide evidence that IL-34 induces a differentiation of myeloid stem cells into monocytic MDSCs (M-MDSCs) that recruits regulatory T (Treg) cells, while suppressing a differentiation into polymorphonuclear MDSCs (PMN-MDSCs). As a result, the increase in M-MDSCs contributes to the creation of an immunosuppressive TME, and the decrease in PMN-MDSCs suppresses angiogenesis, leading to an acquisition of resistance to chemotherapy. Accordingly, blockade of M-MDSC differentiation with an estrogen receptor inhibitor or anti-IL-34 monoclonal antibody suppressed M-MDSCs accumulation causing retardation of tumor growth and restores chemosensitivity of the tumor by promoting PMN-MDSCs accumulation. This study demonstrates previously poorly understood mechanisms of MDSCs-mediated chemoresistance in the TME of TNBC, which is originated from the existence of IL-34, suggesting a new rationale for TNBC treatment.

Mercury causes degradation of spatial cognition in a model songbird species.

Mercury is a widespread pollutant of increasing global concern that exhibits a broad range of deleterious effects on organisms, including birds. Because the developing brain is well-known to be particularly vulnerable to the neurotoxic insults of mercury, many studies have focused on developmental effects such as on the embryonic brain and resulting behavioral impairment in adults. It is not well understood how the timing of exposure, for example exclusively in ovo versus throughout life, influences the impact of mercury. Using dietary exposure to environmentally relevant methylmercury concentrations, we examined the role that timing and duration of exposure play on spatial learning and memory in a model songbird species, the domesticated zebra finch (Taeniopygia guttata castanotis). We hypothesized that developmental exposure was both necessary and sufficient to disrupt spatial memory in adult finches. We documented profound disruption of memory for locations of hidden food at two spatial scales, cage- and room-sized enclosures, but found that both developmental and ongoing adult exposure were required to exhibit this behavioral impairment. Methylmercury-exposed birds made more mistakes before mastering the spatial task, because they revisited unrewarded locations repeatedly even after discovering the rewarded location. Contrary to our prediction, hippocampal volume was not affected in birds exposed to methylmercury over their lifetimes. The disruption of spatial cognition that we detected is severe and would likely have implications for survival and reproduction in wild birds; however, it appears that individuals that disperse or migrate from a contaminated site might recover later in life if no longer exposed to the toxicant.

Postnatal expression of IGF2 is the norm in amniote vertebrates.

The insulin and insulin-like signalling (IIS) network plays an important role in mediating several life-history traits, including growth, reproduction and senescence. Although insulin-like growth factors (IGFs) 1 and 2 are both key hormones in the vertebrate IIS network, research on IGF2 in juveniles and adults has been largely neglected because early biomedical research on rodents found negligible IGF2 postnatal expression. Here, we challenge this assumption and ask to what degree IGF2 is expressed during postnatal life across amniotes by quantifying the relative gene expression of IGF1 and IGF2 using publicly available RNAseq data for 82 amniote species and quantitative polymerase chain reaction on liver cDNA at embryonic, juvenile and adult stages for two lizard, bird and mouse species. We found that (i) IGF2 is expressed postnatally across amniote species and life stages-often at a higher relative expression than IGF1, contradicting rodent models; (ii) the lack of rodent postnatal IGF2 expression is due to phylogenetic placement, not inbreeding or artificial selection; and (iii) adult IGF2 expression is sex-biased in some species. Our results demonstrate that IGF2 expression is typical for amniotes throughout life, suggesting that a comprehensive understanding of the mechanisms mediating variation in life-history traits will require studies that measure both IGFs.

Temperature, size and developmental plasticity in birds.

As temperatures increase, there is growing evidence that species across much of the tree of life are getting smaller. These climate change-driven size reductions are often interpreted as a temporal analogue of the observation that individuals within a species tend to be smaller in the warmer parts of the species' range. For ectotherms, there has been a broad effort to understand the role of developmental plasticity in temperature-size relationships, but in endotherms, this mechanism has received relatively little attention in favour of selection-based explanations. We review the evidence for a role of developmental plasticity in warming-driven size reductions in birds and highlight insulin-like growth factors as a potential mechanism underlying plastic responses to temperature in endotherms. We find that, as with ectotherms, changes in temperature during development can result in shifts in body size in birds, with size reductions associated with warmer temperatures being the most frequent association. This suggests developmental plasticity may be an important, but largely overlooked, mechanism underlying warming-driven size reductions in endotherms. Plasticity and natural selection have very different constraining forces, thus understanding the mechanism linking temperature and body size in endotherms has broad implications for predicting future impacts of climate change on biodiversity.

Experimental Exposure to Noise Alters Gut Microbiota in a Captive Songbird.

Noise pollution is an unprecedented evolutionary pressure on wild animals that can lead to alteration of stress hormone levels and changes in foraging behavior. Both corticosterone and feeding behavior can have direct effects on gut bacteria, as well as indirect effects through changes in gut physiology. Therefore, we hypothesized that exposure to noise will alter gut microbial communities via indirect effects on glucocorticoids and foraging behaviors. We exposed captive white-crowned sparrows to city-like noise and measured each individuals' corticosterone level, food intake, and gut microbial diversity at the end of four treatments (acclimation, noise, recovery, and control) using a balanced repeated measures design. We found evidence that noise acts to increase corticosterone and decrease food intake, adding to a growing body of research indicating noise exposure affects stress hormone levels and foraging behaviors. We also found evidence to support our prediction for a causal, positive relationship between noise exposure and gut microbial diversity, such that birds had higher measures of alpha diversity during noise exposure. These results help to explain previous findings that urban, free-living white-crowned sparrows have higher bacterial richness than rural sparrows. However, noise appeared to act directly on the gut microbiome or, more likely, through an unmeasured variable, rather than through indirect effects via corticosterone and food intake. Altogether, our study indicates that noise affects plasma corticosterone, feeding behavior, and the gut microbiome in a songbird and raises new questions as to the mechanism linking noise exposure to gut microbial diversity.

Interleukin-34 expression in ovarian cancer: a possible correlation with disease progression.

Ovarian cancer is the second-most lethal gynecological malignancy and the seventh-commonest cause of cancer-related death in women around the world. Most of the ovarian cancer patients are diagnosed at advanced stages and suffer from recurrence after primary cytoreductive surgery and standard first-line chemotherapy. Thus, the successful management of ovarian cancer patients requires the identification of factors that contribute to progression and relapse. Interleukin-34 (IL-34) is a novel cytokine that acts as a tissue-specific ligand of colony-stimulating factor-1 receptor (CSF-1R). In cancer, IL-34 exerts pro-tumorigenic functions that promote tumor growth, metastasis, angiogenesis, immune suppression and therapeutic resistance. In this study, we evaluate the impact of IL-34 on progression and survival of ovarian cancer patients. First, IL-34 was found to be expressed in several human ovarian cancer cell lines and cancer tissues from patients. The expression of IL-34 was enhanced by cytotoxic chemotherapy in ovarian cancer cell lines and cancer tissues from chemotherapy-treated ovarian cancer patients. Importantly, high IL-34 expression correlated with worse progression-free survival (PFS) and overall survival in different cohorts. The assessment of PFS based on a combination between IL34 expression and other related genes such as CSF1R and CD163 helped further to reach more statistical significance compared with IL34 alone. Furthermore, in the murine ovarian cancer cell HM-1 in vivo model, it was suggested that IL-34-derived tumor cells was correlated with tumor progression and survival by modulating the immune environment. Collectively, these findings indicate a possible correlation between IL-34 expression and disease progression in ovarian cancer patients and the mouse model.

Detrimental or beneficial? Untangling the literature on developmental stress studies in birds.

Developing animals display a tremendous ability to change the course of their developmental path in response to the environment they experience, a concept referred to as developmental plasticity. This change in behavior, physiology or cellular processes is primarily thought to allow animals to better accommodate themselves to the surrounding environment. However, existing data on developmental stress and whether it brings about beneficial or detrimental outcomes show conflicting results. There are several well-referred hypotheses related to developmental stress in the current literature, such as the environmental matching, silver spoon and thrifty phenotype hypotheses. These hypotheses speculate that the early-life environment defines the capacity of the physiological functions and behavioral tendencies and that this change is permanent and impacts the fitness of the individual. These hypotheses also postulate there is a trade-off among organ systems and physiological functions when resources are insufficient. Published data on avian taxa show that some effects of developmental nutritional and thermal stressors are long lasting, such as the effects on body mass and birdsong. Although hypotheses on developmental stress are based on fitness components, data on reproduction and survival are scarce, making it difficult to determine which hypothesis these data support. Furthermore, most physiological and performance measures are collected only once; thus, the physiological mechanisms remain undertested. Here, we offer potential avenues of research to identify reasons behind the contrasting results in developmental stress research and possible ways to determine whether developmental programming due to stressors is beneficial or detrimental, including quantifying reproduction and survival in multiple environments, measuring temporal changes in physiological variables and testing for stress resistance later in life.

Damage-Fitness Model: the missing piece in integrative stress models.

Over the last decade, several theoretical models have been put forth to describe how animals respond to adverse environments and how this response changes under different physiological demands across life history stages. These models capture the context- and condition-dependent nature of stress responses. Yet, application of the models has been limited thus far in part because each model addresses different aspects of the problems facing the field of stress biology. Thus, there is a need for a unifying theoretical model that incorporates changes in physiological demand with life history stages and age, intricate relationships among physiological systems, and biphasic nature of stress responses. Here, I propose a new integrative framework, the Damage-Fitness Model. In this model, regulators, such as DNA repair mechanisms and glucocorticoids, work together as anti-damage mechanisms to minimize damage at both the cellular and organismal level. When the anti-damage regulators are insufficient or inappropriate, persistent damage accumulates. Previous studies indicate that these damage directly impact reproductive performance, disease risk, and survival. The types of regulators, the threshold at which they are initiated, and the magnitude of the responses are shaped by developmental and current environments. This model unites existing theoretical models by shifting our focus from physiological responses to downstream consequences of the stress responses, circumventing context specificity. Discussions include (1) how the proposed model relates to existing models, (2) steps to test the new model, and (3) how this model can be used to better assess the health of individuals and a population. Lay summary The field of stress physiology faces a challenge of characterizing dynamic cellular, physiological, and behavioral responses when animals encounter a stressor. This paper proposes a new theoretical model which links stress avoidance, damage repair and accumulation, and fitness components.

Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production in iNKT cells.

Invariant natural killer T (iNKT) cells are a subset of innate-like T cells that act as important mediators of immune responses. In particular, iNKT cells have the ability to immediately produce large amounts of IFN-γ upon activation and thus initiate immune responses in various pathological conditions. However, molecular mechanisms that control IFN-γ production in iNKT cells are not fully understood. Here, we report that basic helix-loop-helix transcription factor family, member e40 (Bhlhe40), is an important regulator for IFN-γ production in iNKT cells. Bhlhe40 is highly expressed in stage 3 thymic iNKT cells and iNKT1 subsets, and the level of Bhlhe40 mRNA expression is correlated with Ifng mRNA expression in the resting state. Although Bhlhe40-deficient mice show normal iNKT cell development, Bhlhe40-deficient iNKT cells show significant impairment of IFN-γ production and antitumor effects. Bhlhe40 alone shows no significant effects on Ifng promoter activities but contributes to enhance T-box transcription factor Tbx21 (T-bet)-mediated Ifng promoter activation. Chromatin immunoprecipitation analysis revealed that Bhlhe40 accumulates in the T-box region of the Ifng locus and contributes to histone H3-lysine 9 acetylation of the Ifng locus, which is impaired without T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-γ production in iNKT cells.

Interleukin 34, from pathogenesis to clinical applications.

Interleukin-34 (IL-34) is a hematopoietic cytokine that was described for the first time in 2008 as a second ligand of CSF1R in addition to M-CSF. IL-34 and M-CSF share no sequence homology, but have similar functions, affecting the biology of myeloid cell lineage. In contrast to M-CSF, IL-34 shows unique signaling and expression patterns. Physiologically, IL-34 expression is restricted to epidermis and CNS, acting as a regulator of Langerhans cells and microglia, respectively. However, IL-34 expression can be induced and regulated by NF-κB under pathological conditions. Importantly, growing evidence indicates a correlation between IL-34 and disease severity, chronicity and progression. In addition to its promising roles as a novel diagnostic and prognostic biomarker of disease, IL-34 may also serve as a powerful target for therapeutic intervention. Here, we review the current knowledge regarding the emerging roles of IL-34 in disease, and focus on the clinical applications of IL-34 in medicine.

No Effect of Lifelong Methylmercury Exposure on Oxidative Status in Zebra Finches (Taeniopygia guttata): A Demonstration of Methylmercury-Induced Selection?

Songbirds exposed to methylmercury (MeHg) often exhibit reduced reproductive success and cognitive abilities. To better understand whether oxidative stress plays a role, we dosed zebra finches (Taeniopygia guttata) with a contaminated (1.2 ppm MeHg-cysteine) or control diet for their entire lives, including during development in the egg. Levels of antioxidant enzymes [superoxide dismutase (SOD1 and SOD2)], oxidative damage (4-hydroxynonenal; 4-HNE), and antioxidant transcription factors [nuclear factor (erythroid-derived 2)-like 2; Nrf2] were measured in the liver and pectoralis muscle of adults. MeHg treatment did not affect levels of 4-HNE or liver SOD2 or Nrf2. Birds in the MeHg treatment differed significantly from controls in pectoralis SOD1 and Nrf2, and tended to differ in liver SOD1 and pectoralis SOD2; however, we detected no overall pattern of effect of MeHg on oxidative status in dosed finches. We suspect that this is a consequence of the differential survival of MeHg-tolerant birds.

Myeloid molecular characteristics of human γδ T cells support their acquisition of tumor antigen-presenting capacity.

Human T cells expressing γδ T cell receptor have a potential to show antigen-presenting cell-like phenotype and function upon their activation. However, the mechanisms that underlie the alterations in human γδ T cells remain largely unclear. In this study, we have investigated the molecular characteristics of human γδ T cells related to their acquisition of antigen-presenting capacity in comparison with activated αß T cells. We found that activated γδ but not αß T cells upregulated cell surface expression of a scavenger receptor, CD36, which seemed to be mediated by signaling through mitogen-activated protein kinase and/or NF-κB pathways. Confocal microscopical analysis revealed that activated γδ T cells can phagocytose protein antigens. Activated γδ T cells could induce tumor antigen-specific CD8(+) T cells using both apoptotic and live tumor cells as antigen resources. Furthermore, we detected that C/EBPα, a critical transcription factor for the development of myeloid-lineage cells, is expressed much higher in γδ T cells than in αß T cells. These results unveiled the molecular mechanisms for the elicitation of antigen-presenting functions in γδ T cells and would also help designing new approaches for γδ T cell-mediated human cancer immunotherapy.

Understanding stress in the healthy animal - potential paths for progress.

Although stress is usually associated with disease, the physiological and behavioral responses to stressors are critical mechanisms of resilience for healthy organisms. A recent workshop comprised of researchers who study healthy humans and both free-living and captive non-human animals identified a number of key roadblocks that are impeding progress in understanding how stress responses integrate into the normal physiology of an animal. These include the lack of: (1) an unambiguous definition of a stress phenotype; (2) a robust biomarker, or suite of biomarkers, to indicate that phenotype; (3) theoretical and quantitative models to predict how humans and other animals will react to stressors; (4) a comprehensive understanding of how individual variability in stress responses arise and (5) an understanding of the transitions between acute and chronic stress responses. Collectively, these deficiencies impair our ability to both assess the physiological status of individuals and develop procedures and techniques to reverse the effects elicited by chronic stress before they become pathological. Workshop participants also identified a number of potential approaches to facilitate progress on these problems. They include: (1) increased use of mathematical models to provide quantitative predictions; (2) use of network theory to expose emergent properties not predicted from traditional approaches; (3) development and deployment of improved sensor technology that will allow long-term, dynamic, non-invasive, multi-factor measurements of suites of stress mediators and (4) the recruitment of scientists with diverse skill sets, such as engineers, bioinformaticians, etc.; and (5) the training of young scientists in the multidisciplinary study of stress. Incorporating these approaches in new research should reinvigorate the study of stress and stimulate progress in understanding both how healthy humans cope with stressors and how other animals, including free-living animals, cope with stressors in a rapidly changing environment.

Transient and permanent effects of suboptimal incubation temperatures on growth, metabolic rate, immune function and adrenocortical responses in zebra finches.

In birds, incubation temperature can vary by several degrees Celsius among nests of a given species. Parents may alter incubation temperature to cope with environmental conditions and/or to manipulate embryonic development, and such changes in incubation behavior could have long-lasting effects on offspring phenotype. To investigate short- and long-term effects of suboptimal incubation temperatures on survival and physiological functions in zebra finches, eggs were incubated at 36.2, 37.4 or 38.4 °C for the entire incubation period. The post-hatch environment was identical among the treatment groups. We found that hatching success was lowest in the 38.4 °C group, while post-hatch survival was lowest in the 36.2 °C group. Incubation temperature had sex-specific effects on offspring phenotype: incubation temperatures affected body mass (Mb) but not physiological parameters of males and conversely, the physiological parameters but not Mb of females. Specifically, males from the 38.4 °C group weighed significantly less than males from the 36.2 °C group from the nestling period to adulthood, whereas females from different incubation temperature groups did not differ in Mb. In contrast, females incubated at 36.2 °C had transient but significantly elevated basal metabolic rate and adrenocortical responses during the nestling and fledgling periods, whereas no treatment effect was observed in males. Innate immunity was not affected by incubation temperature in either sex. These results suggest that a 1 °C deviation from what is considered an optimal incubation temperature can lower offspring performance and offspring survival.

Adult T-cell progenitors retain myeloid potential.

During haematopoiesis, pluripotent haematopoietic stem cells are sequentially restricted to give rise to a variety of lineage-committed progenitors. The classical model of haematopoiesis postulates that, in the first step of differentiation, the stem cell generates common myelo-erythroid progenitors and common lymphoid progenitors (CLPs). However, our previous studies in fetal mice showed that myeloid potential persists even as the lineage branches segregate towards T and B cells. We therefore proposed the 'myeloid-based' model of haematopoiesis, in which the stem cell initially generates common myelo-erythroid progenitors and common myelo-lymphoid progenitors. T-cell and B-cell progenitors subsequently arise from common myelo-lymphoid progenitors through myeloid-T and myeloid-B stages, respectively. However, it has been unclear whether this myeloid-based model is also valid for adult haematopoiesis. Here we provide clonal evidence that the early cell populations in the adult thymus contain progenitors that have lost the potential to generate B cells but retain substantial macrophage potential as well as T-cell, natural killer (NK)-cell and dendritic-cell potential. We also show that such T-cell progenitors can give rise to macrophages in the thymic environment in vivo. Our findings argue against the classical dichotomy model in which T cells are derived from CLPs; instead, they support the validity of the myeloid-based model for both adult and fetal haematopoiesis.

A map for lineage restriction of progenitors during hematopoiesis: the essence of the myeloid-based model.

Most hematology and immunology textbooks describe that the first branch point from the hematopoietic stem cells (HSCs) produces two progenitors, one for myelo-erythroid cells and the other for lymphoid cells including T and B cells. This model is based on the concept that the blood cell family can be subdivided into two major lineages, a myelo-erythroid lineage and a lymphoid lineage. Several alternative models have been proposed during the last three decades. We proposed the myeloid-based model in 2001, in which myeloid potential is retained in an early stage of branches toward erythroid, T-, and B-cell lineages. In this review, we focus on the point that cell differentiation models have two different facets: as a map of developmental potential and a cell fate map. These two are expressed in other words as a map for lineage restriction and a map for physiological production routes. We argue that a map of potential is first and foremost essential for the study of molecular mechanisms of lineage commitment, which is the least clarified aspect of cell differentiation. The validity of the myeloid-based model of hematopoiesis will be discussed in reference to these two issues, developmental potential and cell fate.

Modeling Population Growth under Climate Stressors Using Age-structured Matrix Models.

Climate resilience, a focus of many recent studies, has been examined from ecological, physiological, and evolutionary perspectives. However, sampling biases towards adults, males, and certain species have made establishing the link between environmental change and population-level change problematic. Here we used data from four laboratory studies, in which we administered pre- and post-natal stressors, such as suboptimal incubation temperature, heat stress, and food restriction, to zebra finches and quantified hatching success, post-hatch survival, and reproductive success, to parameterize age-structured population dynamics models with the goal of estimating the effect of the stressors on relative population growth rates. Using the same model structure, we tested the hypothesis that early life stages influence population growth rate more than later life stages. Our models suggested that stressful events during embryonic development, such as suboptimal incubation temperatures and reduced gas exchange for the embryos, have a greater total impact on population growth than post-hatch stressors, such as heat stress and food restriction. However, among life history traits, differences in hatching success and sex ratio of offspring in response to stressors changed population growth rates more than differences in any other demographic rate estimates. These results suggest that when predicting population resilience against climate change, it is critical to account for effects of climate change on all life stages, including early stages of life, and to incorporate individuals' physiology and stress tolerance that likely influence future stress responses, reproduction, and survival.