Ultrasound Diagnosis and Near-Infrared Spectroscopy in the Study of Encephalopathy in Neonates Born under Asphyxia: Narrative Review.

Brain injury resulting from adverse events during pregnancy and delivery is the leading cause of neonatal morbidity and disability. Surviving neonates often suffer long-term motor, sensory, and cognitive impairments. Birth asphyxia is among the most common causes of neonatal encephalopathy. The integration of ultrasound, including Doppler ultrasound, and near-infrared spectroscopy (NIRS) offers a promising approach to understanding the pathology and diagnosis of encephalopathy in this special patient population. Ultrasound diagnosis can be very helpful for the assessment of structural abnormalities associated with neonatal encephalopathy such as alterations in brain structures (intraventricular hemorrhage, infarcts, hydrocephalus, white matter injury) and evaluation of morphologic changes. Doppler sonography is the most valuable method as it provides information about blood flow patterns and outcome prediction. NIRS provides valuable insight into the functional aspects of brain activity by measuring tissue oxygenation and blood flow. The combination of ultrasonography and NIRS may produce complementary information on structural and functional aspects of the brain. This review summarizes the current state of research, discusses advantages and limitations, and explores future directions to improve applicability and efficacy.

Mechanisms and physiological relevance of acid-base exchange in functional units of the kidney.

This review discusses the importance of homeostasis with a particular emphasis on the acid-base (AB) balance, a crucial aspect of pH regulation in living systems. Two primary organ systems correct deviations from the standard pH balance: the respiratory system via gas exchange and the kidneys via proton/bicarbonate secretion and reabsorption. Focusing on kidney functions, we describe the complexity of renal architecture and its challenges for experimental research. We address specific roles of different nephron segments (the proximal convoluted tubule, the loop of Henle and the distal convoluted tubule) in pH homeostasis, while explaining the physiological significance of ion exchange processes maintained by the kidneys, particularly the role of bicarbonate ions (HCO3-) as an essential buffer system of the body. The review will be of interest to researchers in the fields of physiology, biochemistry and molecular biology, which builds a strong foundation and critically evaluates existing studies. Our review helps identify the gaps of knowledge by thoroughly understanding the existing literature related to kidney acid-base homeostasis.

Mimicking the cellular environment does not cause monocyte-derived macrophages to become phenotypically similar to Kupffer cells.

Resident macrophages of various mammalian organs are characterized by several distinctive features in their gene expression profile and phenotype, including involvement in the regulation of organ functions, as well as reduced sensitivity to proinflammatory activation factors. The reasons for the formation of such a specific phenotype remain the subject of intensive research. Some papers emphasize the role of the origin of organ macrophages. Other studies indicate that monocytes that develop in the red bone marrow are also able to form resident macrophages with a phenotype characteristic of a particular organ, but this requires appropriate microenvironmental conditions. In this article, we studied the possibility of differentiation of monocyte-derived macrophages into cells with a Kupffer-like phenotype under the influence of the main stromal components of Kupffer cells macrophage niche: Ito cells, liver sinusoid endotheliocytes and hepatocyte growth factor (HGF). It was found that Kupffer cells are characterized by several features, including increased expression of transcription factors Spic and Id3, as well as MUP family genes, Clusterin and Ngp genes. In addition, Kupffer cells were characterized by a higher proliferative activity. The expression of marker genes of Kupffer cells (i.e. Id3, Spic, Marco and Timd4) increased in monocyte-derived macrophages during coculture with Ito cells, liver sinusoid endothelial cells, macrophage colony-stimulating factor and HGF cells only by 3 days. However, the expression level of these genes was always higher in Kupffer cells. In addition, a complete coincidence of the expressed gene profile in monocyte-derived macrophages and Kupffer cells did not occur even after 3 days of culturing.

Gene-Expression Patterns of Tumor and Peritumor Tissues of Smoking and Non-Smoking HPV-Negative Patients with Head and Neck Squamous Cell Carcinoma.

We studied the gene-expression patterns in specimens of tumor and peritumor tissue biopsies of 26 patients with head and neck carcinomas depending on smoking status. Histological and immunohistochemical examinations verified that all tumors belonged to the "classical" subgroup of head and neck carcinomas, and the HPV-negative tumor status was confirmed. The expression of 28 tumor-associated genes determined by RT-PCR was independent of patients' sex or age, TNM status, degree of differentiation, or tissue localization. Moreover, in peritumor tissue, none of the 28 genes were differentially expressed between the groups of smoking and nonsmoking patients. During oncotransformation in both studied groups, there were similar processes typical for HNSCC progression: the expression levels of paired keratins 4 and 13 were reduced, while the expression levels of keratin 17 and CD44 were significantly increased. However, further investigation revealed some distinctive features: the expression of the genes EGFR and TP63 increased significantly only in the nonsmoking group, and the expression of IL6, CDKN2A, EGF, and PITX1 genes changed only in the smoking group. In addition, correlation analysis identified several clusters within which genes displayed correlations in their expression levels. The largest group included 10 genes: TIMP1, TIMP2, WEE1, YAP, HIF1A, PI3KCA, UTP14A, APIP, PTEN, and SLC26A6. The genetic signatures associated with smoking habits that we have found may serve as a prerequisite for the development of diagnostic panels/tests predicting responses to different therapeutic strategies for HNSCC.

Upright proton therapy for esthesioneuroblastoma: a single-institution experience.

Aim: This study presents an analysis (efficacy and toxicity) of outcomes in patients with esthesioneuroblastoma after pencil beam proton therapy with a fixed beamline in the upright position. Background: Esthesioneuroblastoma (ENB) is an extremely rare tumor of sinonasal area located in critical proximity to vital structures. Proton therapy (PT) is often considered the optimal radiation treatment for head-and-neck tumors, although of limited availability. Upright PT delivered using fixed pencil beamline and rotating chair is a fairly promising option. Methods: This is a single-center experience describing the outcomes of PT in 14 patients with ENB treated between January 2016 and October 2022; half of the cases had a history of previous irradiation. The therapy was applied using a fixed pencil beamline with 6D-chair for positioning. The median dose was 63 GyRBE (total range 48-70 GyRBE; based on 1.1 RBE multiplier for protons) with 2.0 GyRBE per fraction. The mean gross tumor volume was 109.5 cm3 (17.1-257.7 cm3). Patient demography, pathology, treatment parameters and toxicity data were analyzed. Radiation-induced reactions were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. Results: The median follow-up time was 28 months. The 1- and 2-year locoregional control rates constituted 100% and 88.9%, respectively; the median duration of local control was 52 months. The 1- and 2-year progression-free survival (PFS) rates constituted 92.9% and 75.0%, respectively; the median PFS duration was 52 months. The 1- and 2-year overall survival (OS) rates constituted 92.9% and 84.4%, respectively. Two patients died of non-cancer-related causes (coronavirus-induced pneumonia) and 1 patient died of tumor progression. All patients tolerated PT well without any treatment gaps. Serious late toxicity reactions included glaucoma in 1 patient and cataract in 2 patients, in over half a year since irradiation. Conclusion: PT with upright design of the unit affords promising outcomes in terms of disease control and toxicity rates in ENB, a sinonasal tumor of complicated localization.

MicroRNA miR-27a as a possible regulator of anti-inflammatory macrophage phenotype in preeclamptic placenta.

INTRODUCTION: The role of the TGFß signaling pathway, an important cascade responsible for the anti-inflammatory polarization of macrophages, in the development of both early- and late-onset preeclampsia (eoPE and loPE), remains poorly understood. In this study, we examined the components of the TGFß signaling cascade and macrophage markers within placental tissue in normal pregnancy and in PE. METHODS: Patients with eoPE, loPE, and normal pregnancy were enrolled in the study (n = 10 in each group). Following techniques were used for the investigation: immunohistochemistry analysis, western blotting, qRT-PCR, isolation of monocytes by magnetic sorting, transfection, microRNA sequencing, and bioinformatic analysis. RESULTS: We observed a significant decrease in the anti-inflammatory macrophage marker CD206 in the loPE group, alongside with a significant down-regulation of CD206 protein production in both eoPE and loPE groups. The level of CD68-positive cells and relative levels of CD163 and MARCO production were comparable across the groups. However, we identified a significant decrease in the TGFß receptor 2 production and its gene expression in the PE group. Further analysis revealed a link between TGFBR2 and MRC1 (CD206) genes through a single miRNA, hsa-miR-27a-3p. Transfecting CD14-derived macrophages with the hsa-miR-27a-3p mimic significantly changed TGFBR2 production, indicating the potential role of this miRNA in regulating the TGFß signaling pathway. We also revealed the up-regulation of hsa-miR-27a-5p and hsa-miR-27a-3p in the trophoblast BeWo b30 cell line under the severe hypoxia condition and the fact that TGFBR2 3' UTR could serve as a potential target for these miRNAs. DISCUSSION: Our findings uncover a novel potential therapeutic target for managing patients with PE, significantly contributing to a deeper comprehension of the underlying mechanisms involved in the development of this pathology.

Stem-Cell-Derived Extracellular Vesicles: Unlocking New Possibilities for Treating Diminished Ovarian Reserve and Premature Ovarian Insufficiency.

Despite advancements in assisted reproductive technology (ART), achieving successful pregnancy rates remains challenging. Diminished ovarian reserve and premature ovarian insufficiency hinder IVF success-about 20% of in vitro fertilization (IVF) patients face a poor prognosis due to a low response, leading to higher cancellations and reduced birth rates. In an attempt to address the issue of premature ovarian insufficiency (POI), we conducted systematic PubMed and Web of Science research, using keywords "stem cells", "extracellular vesicles", "premature ovarian insufficiency", "diminished ovarian reserve" and "exosomes". Amid the complex ovarian dynamics and challenges like POI, stem cell therapy and particularly the use of extracellular vesicles (EVs), a great potential is shown. EVs trigger paracrine mechanisms via microRNAs and bioactive molecules, suppressing apoptosis, stimulating angiogenesis and activating latent regenerative potential. Key microRNAs influence estrogen secretion, proliferation and apoptosis resistance. Extracellular vesicles present a lot of possibilities for treating infertility, and understanding their molecular mechanisms is crucial for maximizing EVs' therapeutic potential in addressing ovarian disorders and promoting reproductive health.

Molecular and phenotypic distinctions of macrophages in tolerant and susceptible to hypoxia rats.

Individual hypoxia tolerance is a major influence on the course and outcome of infectious and inflammatory diseases. Macrophages, which play central roles in systemic inflammatory response and other immunity reactions, are subject to functional activation orchestrated by several transcription factors including hypoxia inducible factors (HIFs). HIF-1 expression levels and the lipopolysaccharide (LPS)-induced systemic inflammatory response severity have been shown to correlate with hypoxia tolerance. Molecular and functional features of macrophages, depending on the organisms resistance to hypoxia, can determine the severity of the course of infectious and inflammatory diseases, including the systemic inflammatory response. The purpose is the comparative molecular and functional characterization of non-activated and LPS-activated bone marrow-derived macrophages under normoxia in rats with different tolerance to oxygen deprivation. Hypoxia resistance was assessed by gasping time measurement in an 11,500 m altitude-equivalent hypobaric decompression chamber. Based on the outcome, the animals were assigned to three groups termed 'tolerant to hypoxia' (n = 12), 'normal', and 'susceptible to hypoxia' (n = 13). The 'normal' group was excluded from subsequent experiments. One month after hypoxia resistance test, the blood was collected from the tail vein to isolate monocytes. Non-activated and LPS-activated macrophage cultures were investigated by PCR, flow cytometry and Western blot methods. Gene expression patterns of non-activated cultured macrophages from tolerant and susceptible to hypoxia animals differed. We observed higher expression of VEGF and CD11b and lower expression of Tnfa, Il1b and Epas1 in non-activated cultures obtained from tolerant to hypoxia animals, whereas HIF-1α mRNA and protein expression levels were similar. LPS-activated macrophage cultures derived from susceptible to hypoxia animals expressed higher levels of Hif1a and CCR7 than the tolerant group; in addition, the activation was associated with increased content of HIF-1α in cell culture medium. The observed differences indicate a specific propensity toward pro-inflammatory macrophage polarization in susceptible to hypoxia rats.

The spleen as a possible source of serine protease inhibitors and migrating monocytes required for liver regeneration after 70% resection in mice.

Introduction: The role of the immune system in liver repair is fundamentally complex and most likely involves the spleen. The close connection between the two organs via the portal vein enables delivery of splenic cytokines and living cells to the liver. This study evaluates expression of inflammation-related genes and assesses the dynamics of monocyte-macrophage and lymphocyte populations of the spleen during the recovery from 70% hepatectomy in mice. Methods: The study used the established mouse model of 70% liver volume resection. The animals were sacrificed 24 h, 72 h or 7 days post-intervention and splenic tissues were collected for analysis: Clariom™ S transcriptomic assay, immunohistochemistry for proliferation marker Ki-67 and macrophage markers, and flow cytometry for lymphocyte and macrophage markers. Results: The loss and regeneration of 70% liver volume affected the cytological architecture and gene expression profiles of the spleen. The tests revealed significant reduction in cell counts for Ki-67+ cells and CD115+ macrophages on day 1, Ly6C + cells on days 1, 3 and 7, and CD3+CD8+ cytotoxic lymphocytes on day 7. The transcriptomic analysis revealed significant activation of protease inhibitor genes Serpina3n, Stfa2 and Stfa2l1 and decreased expression of cell cycle regulatory genes on day 1, mirrored by inverse dynamics observed on day 7. Discussion and conclusion: Splenic homeostasis is significantly affected by massive loss in liver volume. High levels of protease inhibitors indicated by increased expression of corresponding genes on day 1 may play an anti-inflammatory role upon reaching the regenerating liver via the portal vein. Leukocyte populations of the spleen react by a slow-down in proliferation. A transient decrease in the local CD115+ and Ly6C+ cell counts may indicate migration of splenic monocytes-macrophages to the liver.

Phytohormones Affect Differentiation Status of Human Skin Fibroblasts via UPR Activation.

Normalization of secretory activity and differentiation status of mesenchymal cells, including fibroblasts, is an important biomedical problem. One of the possible solutions is modulation of unfolded protein response (UPR) activated during fibroblast differentiation. Here, we investigated the effect of phytohormones on the secretory activity and differentiation of cultured human skin fibroblasts. Based on the analysis of expression of genes encoding UPR markers, abscisic acid (ABA) upregulated expression of the GRP78 and ATF4 genes, while gibberellic acid (GA) upregulated expression of CHOP. Evaluation of the biosynthetic activity of fibroblasts showed that ABA promoted secretion and synthesis of procollagen I and synthesis of fibronectin, as well as the total production of collagen and non-collagen proteins of the extracellular matrix (ECM). ABA also stimulated the synthesis of smooth muscle actin α (α-SMA), which is the marker of myofibroblasts, and increased the number of myofibroblasts in the cell population. On the contrary, GA increased the level of fibronectin secretion, but reduced procollagen I synthesis and the total production of the ECM collagen proteins. GA downregulated the synthesis of α-SMA and decreased the number of myofibroblasts in the cell population. Our results suggest that phytohormones modulate the biosynthetic activity of fibroblasts and affect their differentiation status.

Biochemical and molecular inducers and modulators of M2 macrophage polarization in clinical perspective.

Macrophages as innate immune cells with great plasticity are of great interest for cell therapy. There are two main macrophage populations - pro- and anti-inflammatory cells also known as M1 and M2. High potential in cancer research contributed to the in-depth study of the molecular processes leading to the polarization of macrophages into the M1 phenotype, and much less attention has been paid to anti-inflammatory M2 macrophages, which can be successfully used in cell therapy of inflammatory diseases. This review describes ontogenesis of macrophages, main functions of pro- and and-inflammatory cells and four M2 subpopulations characterized by different functionalities. Data on agents (cytokines, microRNAs, drugs, plant extracts) that may induce M2 polarization through the changes in microenvironment, metabolism, and efferocytosis are summarized. Finally, recent attempts at stable macrophage polarization using genetic modifications are described. This review may be helpful for researchers concerned with the problem of M2 macrophage polarization and potential use of these anti-inflammatory cells for the purposes of regenerative medicine.

The Therapeutic Potential of Multipotent Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Endometrial Regeneration.

Disruption of endometrial regeneration, fibrosis formation, and intrauterine adhesions underlie the development of "thin" endometrium and/or Asherman's syndrome (AS) and are a common cause of infertility and a high risk for adverse obstetric outcomes. The methods used (surgical adhesiolysis, anti-adhesive agents, and hormonal therapy) do not allow restoration of the regenerative properties of the endometrium. The experience gained today with cell therapy using multipotent mesenchymal stromal cells (MMSCs) proves their high regenerative and proliferative properties in tissue damage. Their contribution to regenerative processes is still poorly understood. One of these mechanisms is based on the paracrine effects of MMSCs associated with the stimulation of cells of the microenvironment by secreting extracellular vesicles (EVs) into the extracellular space. EVs, whose source is MMSCs, are able to stimulate progenitor cells and stem cells in damaged tissues and exert cytoprotective, antiapoptotic, and angiogenic effects. This review described the regulatory mechanisms of endometrial regeneration, pathological conditions associated with a decrease in endometrial regeneration, and it presented the available data from studies on the effect of MMSCs and their EVs on endometrial repair processes, and the involvement of EVs in human reproductive processes at the level of implantation and embryogenesis.

Spleen regeneration after subcutaneous heterotopic autotransplantation in a mouse model.

BACKGROUND: Splenectomy may lead to severe postoperative complications, including sepsis and cancers. A possible solution to this problem is heterotopic autotransplantation of the spleen. Splenic autografts rapidly restore the regular splenic microanatomy in model animals. However, the functional competence of such regenerated autografts in terms of lympho- and hematopoietic capacity remains uncertain. Therefore, this study aimed to monitor the dynamics of B and T lymphocyte populations, the monocyte-macrophage system, and megakaryocytopoiesis in murine splenic autografts. METHODS: The model of subcutaneous splenic engraftment was implemented in C57Bl male mice. Cell sources of functional recovery were studied using heterotopic transplantations from B10-GFP donors to C57Bl recipients. The cellular composition dynamics were studied by immunohistochemistry and flow cytometry. Expression of regulatory genes at mRNA and protein levels was assessed by real-time PCR and Western blot, respectively. RESULTS: Characteristic splenic architecture is restored within 30 days post-transplantation, consistent with other studies. The monocyte-macrophage system, megakaryocytes, and B lymphocytes show the highest rates, whereas the functional recovery of T cells takes longer. Cross-strain splenic engraftments using B10-GFP donors indicate the recipient-derived cell sources of the recovery. Transplantations of scaffolds populated with splenic stromal cells or without them afforded no restoration of the characteristic splenic architecture. CONCLUSIONS: Allogeneic subcutaneous transplantation of splenic fragments in a mouse model leads to their structural recovery within 30 days, with full reconstitution of the monocyte-macrophage, megakaryocyte and B lymphocyte populations. The circulating hematopoietic cells provide the likely source for the cell composition recovery.

The prospects of cell therapy for endometriosis.

Endometriosis is a chronic inflammatory estrogen-dependent disease characterized by the growth of endometrial-like tissue outside the physiological region. Despite the fact that this disease is common, laparoscopic surgery is currently the gold standard in the treatment of endometriosis. In this regard, it is necessary to develop new effective methods of minimally invasive therapy for endometriosis. One of the promising areas in the treatment of endometriosis is cell therapy. Cellular therapy is a vast branch of therapeutic methods with various agents. Potential cell therapies for endometriosis may be based on the principle of targeting aspects of the pathogenesis of the disease: suppression of estrogen receptor activity, angiogenesis, fibrosis, and a decrease in the content of stem cells in endometriosis foci. In addition, immune cells such as NK cells and macrophages may be promising agents for cell therapy of endometriosis. Standing apart in the methods of cell therapy is the replacement therapy of endometriosis. Thus, many studies in the field of the pathogenesis of endometriosis can shed light not only on the causes of the disease and may contribute to the development of new methods for personalized cell therapy of endometriosis.

Fluorescence lifetime imaging microscopy as an instrument for human sperm assessment.

Mammalian spermatozoa are highly energized cells in which most of the proteins and activated signaling cascades are involved in the metabolic pathways. Flavin adenine dinucleotide (FAD) has one of the most important roles in the correct functional activity of spermatozoa since it acts as a cofactor for flavoenzymes, critical for proper metabolism and predominantly located in mitochondria. Non-invasive, vital and non-traumatic examination of sperm FAD level and microenvironment could be performed by fluorescence lifetime imaging microscopy (FLIM). In this study, we assessed the metabolic status of spermatozoa from healthy donors and found that FLIM could be used to segregate and separate the male germ cells according to the type of metabolic activity which corresponds with spermatozoa motility measured in standard spermogram tests.

Hysteroscopic injections of autologous endometrial cells and platelet-rich plasma in patients with thin endometrium: a pilot randomized study.

The aim of this study was to evaluate the efficacy of hysteroscopically controlled injections of autologous platelet-rich plasma (PRP) and autologous endometrial cells as a treatment for infertile women with thin endometrium. The study enrolled 115 patients with thin endometrium (< 7 mm at implantation window) and infertility, who were divided into groups: Group 1 (the control) underwent conservative therapy; Group 2 received intraendometrial PRP injections instead of the conservative therapy; Group 3 received identical injections after conservative therapy; Group 4 received injections of the autologous endometrial cells suspended in PRP. A single injection dose of PRP contained 0.6-0.7 × 1011 of platelets. The levels of PDGF-BB and VEGF in PRP were increased compared with ordinary plasma. The autologous endometrial cells, obtained from pipelle biopsies, constituted heterogeneous cell populations containing stromal and epithelial cells. Intraendometrial PRP injections had significant impact on endometrial thickness and local microcirculation in Group 2 and Group 3. In Group 4, injections of PRP reinforced with endometrial cells also facilitated a significant increase in endometrial thickness. This work describes a novel approach for infertility treatment in patients with refractory thin endometrium. PRP injections and injections of the endometrial cells suspended in PRP into endometrium enhanced cell proliferation and angiogenesis.

Spleen regeneration after subcutaneous heterotopic autotransplantation in a mouse model

BACKGROUND: Splenectomy may lead to severe postoperative complications, including sepsis and cancers. A possible solution to this problem is heterotopic autotransplantation of the spleen. Splenic autografts rapidly restore the regular splenic microanatomy in model animals. However, the functional competence of such regenerated autografts in terms of lympho- and hematopoietic capacity remains uncertain. Therefore, this study aimed to monitor the dynamics of B and T lymphocyte populations, the monocyte-macrophage system, and megakaryocytopoiesis in murine splenic autografts. METHODS: The model of subcutaneous splenic engraftment was implemented in C57Bl male mice. Cell sources of functional recovery were studied using heterotopic transplantations from B10-GFP donors to C57Bl recipients. The cellular composition dynamics were studied by immunohistochemistry and flow cytometry. Expression of regulatory genes at mRNA and protein levels was assessed by real-time PCR and Western blot, respectively. RESULTS: Characteristic splenic architecture is restored within 30 days post-transplantation, consistent with other studies. The monocyte-macrophage system, megakaryocytes, and B lymphocytes show the highest rates, whereas the functional recovery of T cells takes longer. Cross-strain splenic engraftments using B10-GFP donors indicate the recipient-derived cell sources of the recovery. Transplantations of scaffolds populated with splenic stromal cells or without them afforded no restoration of the characteristic splenic architecture. CONCLUSIONS: Allogeneic subcutaneous transplantation of splenic fragments in a mouse model leads to their structural recovery within 30 days, with full reconstitution of the monocyte-macrophage, megakaryocyte and B lymphocyte populations. The circulating hematopoietic cells provide the likely source for the cell composition recovery.

Particle Therapy: Clinical Applications and Biological Effects.

Particle therapy is a developing area of radiotherapy, mostly involving the use of protons, neutrons and carbon ions for cancer treatment. The reduction of side effects on healthy tissues in the peritumoral area is an important advantage of particle therapy. In this review, we analyze state-of-the-art particle therapy, as compared to conventional photon therapy, to identify clinical benefits and specify the mechanisms of action on tumor cells. Systematization of published data on particle therapy confirms its successful application in a wide range of cancers and reveals a variety of biological effects which manifest at the molecular level and produce the particle therapy-specific molecular signatures. Given the rapid progress in the field, the use of particle therapy holds great promise for the near future.

An Eye on Kupffer Cells: Development, Phenotype and the Macrophage Niche.

Macrophages are key participants in the maintenance of tissue homeostasis under normal and pathological conditions, and implement a rich diversity of functions. The largest population of resident tissue macrophages is found in the liver. Hepatic macrophages, termed Kupffer cells, are involved in the regulation of multiple liver functionalities. Specific differentiation profiles and functional activities of tissue macrophages have been attributed to the shaping role of the so-called tissue niche microenvironments. The fundamental macrophage niche concept was lately shaken by a flood of new data, leading to a revision and substantial update of the concept, which constitutes the main focus of this review. The macrophage community discusses contemporary evidence on the developmental origins of resident macrophages, notably Kupffer cells and the issues of heterogeneity of the hepatic macrophage populations, as well as the roles of proliferation, cell death and migration processes in the maintenance of macrophage populations of the liver. Special consideration is given to interactions of Kupffer cells with other local cell lineages, including Ito cells, sinusoidal endothelium and hepatocytes, which participate in the maintenance of their phenotypical and functional identity.