The Sterile 20-Like Kinase Tao Controls Tissue Homeostasis by Regulating the Hippo Pathway in Drosophila Adult Midgut

The proliferation and differentiation of adult stem cells must be tightly controlled in order to maintain resident tissue homeostasis. Dysfunction of stem cells is implicated in many human diseases, including cancer. However, the regulation of stem cell proliferation and differentiation is not fully understood. Here we show that the sterile-like 20 kinase, Tao, controls tissue homeostasis by regulating the Hippo pathway in the Drosophila adult midgut. Depletion of Tao in the progenitors leads to rapid intestinal stem cell （ISC） proliferation and midgut homeostasis loss. Meanwhile, we find that the Janus kinase （JAK）/signal transducer and activator of transcription （STAT） signaling activity and cytokine production are significantly increased, resulting in stimulated ISC proliferation. Furthermore, expression of the Hippo pathway downstream targets, Diapl and bantam, is dramatically increased in Tao knockdown intestines. Consistently, we show that the Yorkie （Yki） acts downstream of Tao to regulate ISC proliferation. Together, our results provide insights into our understanding of the mechanisms of stem cell proliferation and tissue homeostasis control.

Unraveling the complex roles of macrophages in obese adipose tissue:an overview

Macrophages,a heterogeneous population of innate immune cells,exhibit remarkable plasticity and play pivotal roles in coordinating immune responses and maintaining tissue homeostasis within the context of metabolic diseases.The activation of inflammatory macrophages in obese adipose tissue leads to detrimental effects,inducing insulin resistance through increased inflammation,impaired thermogenesis,and adipose tissue fibrosis.Meanwhile,adipose tissue macrophages also play a beneficial role in maintaining adipose tissue homeostasis by regulating angiogenesis,facilitating the clearance of dead adipocytes,and promoting mitochondrial transfer.Exploring the heterogeneity of macrophages in obese adipose tissue is crucial for unraveling the pathogenesis of obesity and holds significant potential for targeted therapeutic interventions.Recently,the dual effects and some potential regulatory mechanisms of macrophages in adipose tissue have been elucidated using single-cell technology.In this review,we present a comprehensive overview of the intricate activation mechanisms and diverse functions of macrophages in adipose tissue during obesity,as well as explore the potential of drug delivery systems targeting macrophages,aiming to enhance the understanding of current regulatory mechanisms that may be potentially targeted for treating obesity or metabolic diseases.

Cell competition in liver carcinogenesis

Cell competition is now a well-established quality control strategy to optimize cell and tissue fitness in multicellular organisms.While pursuing this goal,it is also effective in selecting against altered/defective cells with putative(pre)-neoplastic potential,thereby edging the risk of cancer development.The flip side of the coin is that the molecular machinery driving cell competition can also be co-opted by neoplastic cell populations to expand unchecked,outside the boundaries of tissue homeostatic control.This review will focus on information that begins to emerge regarding the role of cell competition in liver physiology and pathology.Liver repopulation by normal transplanted hepatocytes is an interesting field of investigation in this regard.The biological coordinates of this process share many features suggesting that cell competition is a driving force for the clearance of endogenous damaged hepatocytes by normal donor-derived cells,as previously proposed.Intriguing analogies between liver repopulation and carcinogenesis will be briefly discussed and the potential dual role of cell competition,as a barrier or a spur to neoplastic development,will be considered.Cell competition is in essence a cooperative strategy organized at tissue level.One facet of such cooperative attitude is expressed in the elimination of altered cells which may represent a threat to the organismal community.On the other hand,the society of cells can be disrupted by the emergence of selfish clones,exploiting the molecular bar codes of cell competition,thereby paving their way to uncontrolled growth.

Linking tyrosine kinase inhibitor-mediated inflammation with normal epithelial cell homeostasis and tumor therapeutic responses

Receptor tyrosine kinases(RTKs)bearing oncogenic mutations in EGFR,ALK and ROS1 occur in a significant subset of lung adenocarcinomas.Tyrosine kinase inhibitors(TKIs)targeting tumor cells dependent on these oncogenic RTKs yield tumor shrinkage,but also a variety of adverse events.Skin toxicities,hematological deficiencies,nausea,vomiting,diarrhea,and headache are among the most common,with more acute and often fatal side effects such as liver failure and interstitial lung disease occurring less frequently.In normal epithelia,RTKs regulate tissue homeostasis.For example,EGFR maintains keratinocyte homeostasis while MET regulates processes associated with tissue remodeling.Previous studies suggest that the acneiform rash occurring in response to EGFR inhibition is a part of an inflammatory response driven by pronounced cytokine and chemokine release and recruitment of distinct immune cell populations.Mechanistically,blockade of EGFR causes a Type I interferon response within keratinocytes and in carcinoma cells driven by this RTK.This innate immune response within the tumor microenvironment(TME)involves increased antigen presentation and effector T cell recruitment that may participate in therapy response.This TKI-mediated release of inflammatory suppression represents a novel tumor cell vulnerability that may be exploited by combining TKIs with immune-oncology agents that rely on T-cell inflammation for efficacy.However,early clinical data indicate that combination therapies enhance the frequency and magnitude of the more acute adverse events,especially pneumonitis,hepatitis,and pulmonary fibrosis.Further preclinical studies to understand TKI mediated inflammation and crosstalk between normal epithelial cells,cancer cells,and the TME are necessary to improve treatment regimens for patients with RTK-driven carcinomas.