Homing Ability Research Articles

Myeloma cell-derived CXCL7 facilitates proliferation of tumor cells and occurrence of osteolytic lesions through JAK/STAT3 pathway

Osteolytic lesions and pathological fractures are hallmark manifestations of multiple myeloma (MM), profoundly influencing the quality of life and self-care ability of MM patients. By analyzing transcriptome data and single-cell RNA-seq data from our center and the GEO database, a subset of MM cells with high expression levels of chemokine CXCL7 was identified. This subset of MM cells possesses a high capacity for proliferation and activation of osteoclast signaling pathway. CXCL7 might be a crucial regulator of osteolytic damage in MM. Subsequently, the association between the expression level of CXCL7 and pathological fractures in patients was investigated, and the impact of CXCL7 on MM proliferation was confirmed both in vivo and in vitro. A mouse xenograft tumor model was established through intravenous injection of myeloma cell lines based on the homing ability of plasma cells. Moreover, the mechanism by which CXCL7 promotes the activation of osteoclast signaling pathways in MM was explored. Our findings reveal that elevated CXCL7 levels significantly enhance MM cell proliferation, increasing the risk of pathological fractures in MM patients. Additionally, our mouse xenograft tumor model demonstrated that CXCL7 can induce femoral fractures and reduce bone mineral density. Concurrently, it was discovered that CXCL7 could activate the JAK/STAT3 pathway via CXCR2 and upregulate the expression levels of MMP13 and C-myc, facilitating MM cell proliferation and activation of the osteoclast signaling pathway. Our study offers novel insights into the pathogenic mechanism of osteolytic lesions and implies that targeting CXCL7 may present a new therapeutic avenue for MM.

Divergence of sexual size dimorphism between wild and hatchery chum salmon under intensive Japanese hatchery programs

Artificial propagation weakens sexual selection by reducing male-male competition and female choice, which favor larger males in natural reproduction. If homing ability and sexual selection were strong, wild-origin salmon would exhibit more pronounced male-biased sexual size dimorphism (SSD) than their hatchery-origin counterparts. We conducted field sampling of chum salmon (Oncorhynchus keta) in two Japanese rivers, where hatchery fish were marked using otolith thermal marking. The length at maturity of hatchery salmon differed by only 1–2 cm between males and females, whereas the length at maturity of wild-dominated salmon was 5–6 cm larger in males than in females. The mean age at maturity of wild-dominated fish was 0.2–0.3 years higher than that of hatchery fish, but no significant sex differences were observed in either origin. Additionally, macro-level comparisons of SSD, calculated as log<sub>10</sub>(male length/female length), among 21 populations showed that wild-dominated populations had significantly higher SSD than hatchery-dominated populations. Overall, hatchery salmon exhibited weaker SSD, consistent with reduced sexual selection in the hatchery.

LGR4 promotes proliferation and homing via activation of the NF‑κB signaling pathway in multiple myeloma.

Multiple myeloma (MM) is a plasma cell malignancy characterized by clonal proliferation in the bone marrow (BM). Previously, it was reported that G‑protein‑coupled receptor 4 (LGR4) contributed to early hematopoiesis and was associated with poor prognosis in patients with MM. However, the mechanism of cell homing and migration, which is critical for MM progression, remains unclear. In the present study, cell counting, cell cycle and BrdU assays were performed to evaluate cell proliferation. Transwell assay and Xenograft mouse models were performed to evaluate cell migration and homing ability both in vitro and in vivo. I was found that overexpression of LGR4 promotes MM cell adhesion, migration and homing to BM both in vitro, while exacerbating osteolytic bone destruction in vivo. However, the LGR4 knockdown displayed the opposite effect. Further mechanistic studies demonstrated that LGR4 activated the nuclear factor kappa B (NF‑κB) signaling pathway and migration‑related adhesion molecule, thus promoting MM cell homing. Moreover, inhibiting the NF‑κB pathway was found to suppress MM cell homing. These findings identify LGR4 as a critical regulator of myeloma cell migration, homing and tumorigenesis, offering a potential therapeutic strategy for MM treatment.

A Novel Oncolytic Virus Formulation Based on Mesenchymal Stem Cell-Derived Vesicles for Tumor Therapy.

Developing new drug delivery systems is crucial for enhancing the efficacy of oncolytic virus (OV) therapies in cancer treatment. In this study, mesenchymal stem cell (MSC)-derived vesicles and oncolytic viruses are exploited to construct a novel formulation. It has been hypothesized that vesicle-coated OVs could amplify cytotoxic effects through superior internalization by tumor cells. MSC vesicles possess natural tumor homing ability and biocompatibility, which can enhance the targeting, uptake, and therapeutic effects of OVs on tumor cells. Experimental results indicated that this treatment system has increased the apoptosis of tumor cells. Furthermore, flow cytometry analysis demonstrated that the uptake of tumor cells by OVs coated with MSC vesicles soared away compared to uncoated OVs, being 1.5 times than that of the uncoated group. Additionally, the confocal laser scanning microscopy also showed that the fluorescence intensity within tumor cells pretreated with MSC-coated OVs was greater. Meanwhile, propidium iodide (PI) staining revealed that MSC-coated Ovs exposed to tumor cells accelerating the apoptosis of the latter. According to the statistics, the number of dead cells was increased, and the flow cytometry testified that the apoptosis in the MSC-coated OV group was as high as 23.78%. These findings highlight the potential of MSC vesicle-coated OVs in enhancing the delivery and efficacy of oncolytic virus therapy, providing a promising strategy for cancer treatment.

Determining homing abilities of nesting male threespine stickleback ( Gasterosteus aculeatus )

Determining homing abilities of nesting male threespine stickleback ( Gasterosteus aculeatus )

Natural endogenous material-based vehicles for delivery of macromolecular drugs.

Natural endogenous materials (NEMs), such as cell and cell derivatives, polysaccharide, protein and peptide, and nucleic acid-derived vectors, often exhibit biocompatibility, biodegradability and natural homing ability, which can minimize adverse reactions in vivo and have the potential to improve drug delivery efficacy. Currently, a variety of drug delivery systems (DDSs) based on NEMs have been constructed for macromolecules to address the challenges posed by their inherent large size, intricate structure, low permeability, and susceptibility to harsh environments. The aim of this article is to provide a comprehensive overview of various delivery strategies that predominantly utilize NEMs as carriers for macromolecular delivery. By thoroughly discussing the pros and cons of NEM-based DDSs, we hope to provide valuable insights into future innovations in pharmaceutical science, with a focus on improving therapeutic outcomes through advanced drug formulations.

Optimized protocol for the isolation and expansion of menstrual blood-derived mesenchymal stem cells for combination with oncolytic adenoviruses in cancer treatment

Oncolytic viruses (OVs) are a promising therapeutic approach for cancer, although their systemic administration faces significant challenges. Mesenchymal stem cells have emerged as potential carriers to overcome these obstacles due to their tumor-tropic properties. This study investigates the use of menstrual blood-derived mesenchymal stem cells (MenSCs) as carriers for oncolytic viruses in cancer therapy, focusing on enhancing their efficacy through different culture conditions. MenSCs were isolated from donors of different ages and cultured under normoxic and hypoxic conditions, with varying adherence capacities. Hypoxic conditions significantly improved MenSCs proliferation and tumor migration capabilities, as demonstrated by proliferation assays and RNA-Seq analysis, which revealed upregulation of genes related to cell division and tumor tropism. In vivo studies using a lung adenocarcinoma mouse model confirmed that hypoxia-conditioned MenSCs had superior tumor homing abilities. The study also demonstrated the feasibility of establishing a master and working cell bank from a single menstrual blood donation. These findings suggest that hypoxia-conditioned MenSCs could be highly effective as OV carriers, potentially leading to better clinical outcomes in cancer treatment by enhancing tumor targeting and therapeutic efficacy.

Bone marrow mesenchymal stem cells overexpressing stromal cell- derived factor 1 aid in bone formation in osteoporotic mice

BackgroundOsteoporosis is characterized by low systemic bone mineral content and destruction of bone microarchitecture. Promoting bone regeneration and reversing its loss by infusion of exogenous bone marrow mesenchymal stem cells (BMSCs) is a potentially effective treatment for osteoporosis. However, their limited migration to target organs reduces the therapeutic effect of the cells. Stromal cell-derived factor 1 (SDF1) is a chemokine that induces targeted cell migration through the SDF1/CXCR4 (C-X-C chemokine receptor 4) axis and can induce migration of exogenous mesenchymal stem cells to sites of high SDF1 concentration. There are no studies on BMSCs overexpressing SDF1 (SDF1-BMSCs) in osteoporotic mice in vivo. We aimed to investigate if the increased SDF1 concentration facilitated cell migration to the bone.MethodsWe used lentivirus to construct BMSCs overexpressing SDF1 or knocking down CXCR4. We verified the proliferation ability of the cells in vitro using Cell Counting Kit-8 (CCK8) and 5-Bromodeoxyuridinc (BrdU), the migration ability of the cells using Transwell, and the osteogenic and lipogenic ability of the cells using osteogenic and lipogenic induction solutions. In in vivo experiments, we induced osteoporosis in 72 female mice by ovariectomy and injected different groups of cells via the tail vein. Femoral tissue samples were collected for a fixed time, and the osteogenic and homing abilities of the cells were verified by MicroCT and tissue section staining.ResultsWe successfully demonstrated that high expression of SDF1 promoted cell proliferation and migration in vitro, without affecting their cell differentiation ability. In an ovariectomized mouse model, SDF1-BMSCs were more likely to be home to the femur than the BMSCs, had a better pro-osteogenic ability, and had higher expression of Wnt-1. Blocking the SDF1/CXCR4 axis reduced the homing of exogenous mesenchymal stem cells (MSCs) to the femur and their osteogenic capacity.ConclusionsSDF1-BMSCs can further promote bone formation by increasing the number of cells homing to the femur in osteoporotic mice. Our study shows that stem cells can promote their proliferation and home to the femur via the SDF1/CXCR4 axis and further help bone formation via Wnt-1 signaling.

Discovery of a multipotent cell type from the term human placenta.

We report a population of multipotent cells isolated from term human placentas, for the first time, that differentiates into cardiomyocytes and vascular cells with clonal ability, migratory ability, and trancriptomic evidence of immune privilege. Caudal-type homeobox-2 (CDX2) is a conserved factor that regulates trophectoderm formation and placentation during early embryonic development but has not previously been implicated in developmentally conserved regenerative mechanisms. We earlier reported that murine Cdx2 cells restored cardiac function after intravenous delivery in male mice with experimental myocardial infarction (MI). Here we demonstrate that CDX2 cells found in human chorion are poised for cardiovascular differentiation. We isolated CDX2 cells from term placentas of 150 healthy patients and showed that they spontaneously differentiate into cardiomyocytes, functional vascular cells, and retain homing ability in vitro with a transcriptome that supports enhanced cardiogenesis, vasculogenesis, immune modulation, and chemotaxis gene signatures. They restore cardiac function when administered to NOD/SCID mice subjected to MI. CDX2 cells can be clonally propagated in culture with retention of cardiovascular differentiation. Our data compels further use of this ethically feasible cell source in the design of therapeutic strategies for cardiovascular disease.

Acoustic cognitive map-based navigation in echolocating bats.

Bats are known for their ability to use echolocation for obstacle avoidance and orientation. However, the extent to which bats utilize their highly local and directional echolocation for kilometer-scale navigation is unknown. In this study, we translocated wild Kuhl's pipistrelle bats and tracked their homing abilities while manipulating their visual, magnetic, and olfactory sensing and accurately tracked them using a new reverse GPS system. We show that bats can identify their location after translocation and conduct several-kilometer map-based navigation using solely echolocation. This proposition was further supported by a large-scale echolocation model disclosing how bats use environmental acoustic information to perform acoustic cognitive map-based navigation. We also demonstrate that navigation is improved when using both echolocation and vision.

Tumor-Derived Extracellular Vesicles Enable Tumor Tropism Chemo-Genetherapy for Local Immune Activation in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is highly heterogeneous, lacks accessible therapeutic targets, and features an immunosuppressive tumor microenvironment (TME). Anthracycline-based chemotherapy remains the primary treatment method for TNBC, while the current popular immune checkpoint inhibitors persistently encounter therapeutic resistance. Therefore, there is an urgent need to explore combined therapeutic strategies to remodel the TME and improve the treatment response. Considering the highly specific homing ability of tumor cell-derived vesicles and the key role of the signal transduction and activation of the transcription factor 3 (STAT3) pathway in TNBC, we propose a synergistic therapeutic strategy that integrates gene therapy, chemotherapy, and immunotherapy based on STAT3 short interfering RNA (siSTAT3) and doxorubicin (DOX)-functionalized tumor-derived extracellular vesicles (TEVs) (siSTAT3-DOX@TEV). The in vitro and in vivo results demonstrate that siSTAT3-DOX@TEV target tumor tissues precisely, downregulate STAT3 expression, and synergistically and efficiently induce immunogenic death, thereby reversing the immunosuppressive TME. Moreover, mass cytometry and immunohistochemistry reveal the local immune activation effect of siSTAT3-DOX@TEV, with a significant increase in M1 macrophages, CD4+ T cells, and CD8+ T cells in tumor tissues. These results provide strong hints for the development of TEV-based chemo-gene therapeutic agents for TNBC treatment at the clinical level.

Bacterial outer membrane vesicles-clothed nanoparticles delivered by live macrophages for potentiating antitumor photoimmunotherapy

Tumor-associated macrophage (TAM) plays an important role in tumor immune regulation. Reprogramming TAMs to reshape immunosuppressive tumor microenvironment (TME) is a promising antitumor strategy. Herein, imiquimod (R837) and black phosphorus quantum dots (BPQDs) are encapsulated in bacterial outer membrane vesicles (OMVs)-clothed liposomes to obtain RB@OL nanoparticles, which are further delivered by M1-type macrophages through phagocytic loading (RB-OL@M). Owing to the natural homing ability of macrophages to tumor sites, RB-OL@M actively targets cancerous region after intravenous injection. Meanwhile, upon laser irradiation, RB@OL is released from macrophages to exert combinational photoimmunotherapy due to the excellent phototherapeutic property of BPQDs and TAM regulating potential of R837. Benefiting from this versatile strategy, RB-OL@M effectively delays the growth of 4 T1 breast tumors and prevents the occurrence of their dreadful lung metastasis, largely prolonging the survival of 4 T1 tumor-bearing mice. Overall, this work offers a promising antitumor approach based on live cell-mediated multirole nanoplatform.

Enforced hematopoietic cell E-selectin/L-selectin ligand expression enhances bone marrow stromal cells homing and amelioration of cerebral ischemia-reperfusion injury via induction of prostaglandin E2.

Ischemic stroke (IS) is a significant and potentially life-threatening disease with limited treatment options, often resulting in severe disability. Bone marrow stromal cells (BMSCs) transplantation has exhibited promising neuroprotection following cerebral ischemia-reperfusion injury (CIRI). However, the effectiveness is hindered by their low homing rate when administered through the vein. In this study, we aimed to enhance the homing ability of BMSCs through lentivirus transfection to express fucosyltransferase 7. This glycosylation engineered CD44 on BMSCs to express hematopoietic cell E-selectin/L-selectin ligand (HCELL), which is the most potent E-selectin ligand. Following enforced HCELL expression, the transplantation of BMSCs was then evaluated in a middle cerebral artery occlusion model. Results showed that HCELL+BMSCs significantly ameliorated neurological deficits and reduced the volume of cerebral infarction. Furthermore, the transplantation led to a decrease in apoptosis by upregulating BCL-2 and downregulating BAX, also reduced the mRNA levels of inflammatory factors, such as interleukin-1β (IL-1β), IL-2, IL-6, and tumor necrosis factor-alpha (TNF-α) in the ischemic brain tissue. Notably, enforced HCELL expression facilitated the migration of BMSCs toward cerebral ischemic lesions and their subsequent transendothelial migration through the upregulation of PTGS-2, increased production of PGE2 and activation of VLA-4. In summary, our study demonstrates that transplantation of HCELL+BMSCs effectively alleviates CIRI, and that enforced HCELL expression enhances the homing of BMSCs to cerebral ischemic lesions and their transendothelial migration via PTGS-2/PGE2/VLA-4. These findings indicate that enforced expression of HCELL on BMSCs could serve as a promising therapeutic strategy for the treatment of ischemic stroke.

B7-H3-Targeted CAR-Vδ1T Cells Exhibit Potent Broad-Spectrum Activity against Solid Tumors.

Vδ1T cells, a rare subset of γδT cells, hold promise for treating solid tumors. Unlike conventional T cells, they recognize tumor antigens independently of the MHC antigen presentation pathway, making them a potential "off-the-shelf" cell therapy product. However, isolation and activation of Vδ1T cells is challenging, which has limited their clinical investigation. Here, we developed a large-scale clinical-grade manufacturing process for Vδ1T cells and validated the therapeutic potential of B7-H3 chimeric antigen receptor (CAR)-modified Vδ1T cells in treating solid tumors. Coexpression of IL2 with the B7-H3-CAR led to durable antitumor activity of Vδ1T cells in vitro and in vivo. In multiple subcutaneous and orthotopic mouse xenograft tumor models, a single intravenous administration of the CAR-Vδ1T cells resulted in complete tumor regression. These modified cells demonstrated significant in vivo expansion and robust homing ability to tumors, akin to natural tissue-resident immune cells. Additionally, the B7-H3-CAR-Vδ1T cells exhibited a favorable safety profile. In conclusion, B7-H3-CAR-modified Vδ1T cells represent a promising strategy for treating solid tumors. Significance: A clinical-grade expansion protocol enabled generation of B7-H3-targeted CAR-Vδ1T cells with robust anticancer activity and a favorable safety profile, supporting the potential of CAR-Vδ1T cells as an "off-the-shelf" therapy for solid tumors.

Microchip Based Isolation and Drug Delivery of Patient-Derived Extracellular Vesicles Against Their Homologous Tumor.

Extracellular vesicles (EVs) have demonstrated significant potential in drug delivery and anti-tumor therapy. Despite this promising strategy, challenges such as specific targeting, EVs purification persist. In this study, a personalized nanodrug delivery platform using patient-derived tumor EVs (PT-EVs) based on a microchip is presented. The microchip integrates multiple functions, including capture, enrichment, drug loading, and elution of PT-EVs. The isolation and drug-carrying procedures are completed within a 12 h timeframe, achieving a recovery rate of 65%, significantly surpassing the conventional ultracentrifuge (UC) method. Furthermore, PT-EVs derived from patient tumor models are first utilized as natural drug carriers, capitalizing on their inherent homing ability to precisely target homologous tumors. Lenvatinib and doxorubicin (DOX), two commonly utilized drugs in the clinical treatment of hepatocellular carcinoma (HCC), are loaded into PT-EVs and delivered to a matched in vitro tumor model that recapitulates original tumors for drug susceptibility testing. As is proven, PT-EVs exhibit robust tumor cell targeting and efficient receptor-mediated cellular uptake, and the efficacy of chemotherapeutic drugs is improved significantly. These results suggest that this platform could be a valuable tool for efficient isolation of PT-EVs and personalized drug customization, particularly when working with limited clinical samples, thus supporting personalized and precision medicine.

IL-21- and CXCL9-engineered GPC3-specific CAR-T cells combined with PD-1 blockade enhance cytotoxic activities against hepatocellular carcinoma

The application of CAR-T cells in solid tumors poses several challenges, including poor T cell homing ability, limited infiltration of T cells and an immunosuppressive tumor environment. In this study, we developed a novel approach to address these obstacles by designing GPC3-specific CAR-T cell that co-express IL-21 and CXCL9 (21 × 9 GPC3 CAR-T cells) and blocking the PD-1 expression on it. The proliferation, cell phenotype, cytokine secretion and cell migration of indicated CAR-T cells were evaluated in vitro. The cytotoxic activities of genetically engineered CAR-T cells were accessed in vitro and in vivo. Compared to conventional GPC3 CAR-T cells, the 21 × 9 GPC3 CAR-T cells demonstrated superior proliferation, cytokine secretion and chemotaxis capabilities in vitro. Furthermore, when combined with PD-1 blockade, the 21 × 9 GPC3 CAR-T cells exhibited enhanced proliferation, cytokine secretion and enrichment of effector T cells such as CTL, NKT and TEM cells. In xenograft tumor models, the PD-1 blocked 21 × 9 GPC3 CAR-T cells effectively suppressed HCC xenograft growth and increased T cell infiltration. Overall, our study successfully generated GPC3 CAR-T cells expressing both IL-21 and CXCL9, demonstrated that combining PD-1 blockade can further enhance CAR-T cell function by promoting proliferation, cytokine secretion, chemotaxis and antitumor activity. These findings present a hopeful and potentially effective strategy for GPC3-positive HCC patients.

Human glioblastoma-derived cell membrane nanovesicles: a novel, cell-specific strategy for boron neutron capture therapy of brain tumors

Glioblastoma (GBM), one of the deadliest brain tumors, accounts for approximately 50% of all primary malignant CNS tumors, therefore novel, highly effective remedies are urgently needed. Boron neutron capture therapy, which has recently repositioned as a promising strategy to treat high-grade gliomas, requires a conspicuous accumulation of boron atoms in the cancer cells. With the aim of selectively deliver sodium borocaptate (BSH, a 12 B atoms-including molecule already employed in the clinics) to GBM cells, we developed novel cell membrane-derived vesicles (CMVs), overcoming the limits of natural extracellular vesicles as drug carriers, while maintaining their inherent homing abilities that make them preferable to fully synthetic nanocarriers. Purified cell membrane fragments, isolated from patient-derived GBM stem-like cell cultures, were used to prepare nanosized CMVs, which retained some membrane proteins specific of the GBM parent cells and were devoid of potentially detrimental genetic material. In vitro tests evidenced the targeting ability of this novel nanosystem and ruled out any cytotoxicity. The CMVs were successfully loaded with BSH, by following two different procedures, i.e. sonication and electroporation, demonstrating their potential applicability in GBM therapy.

Displaced juvenile and subadult Caribbean spiny lobsters show strong orientation toward home dens

Caribbean spiny lobsters are known to undergo migration as adults, but the dispersal and homing ability of subadults and juveniles is not well characterized. Given that settlement habitat for juveniles is inshore seagrass / hardbottom and reproductive habitat is offshore coral reefs, dispersal during ontogeny serves as a bottleneck potentially limiting adult population density. Previous studies have examined factors associated with movement and den selection by juvenile lobsters such as shelter type, predators, and conspecific density. Their attraction to odors of healthy conspecifics plays a significant role in aggregation of lobsters in casitas and traps. But what is unknown is whether juvenile lobsters possess the map and compass orientation found in adults. To examine the ontogeny of homing ability, we conducted multiple mark / displace tracking studies using acoustic telemetry in juvenile hardbottom and subadult coral patch reef habitats. All lobsters regardless of size tend to relocate to new crevice shelters when handled, even if returned to their original shelter. Thus, for non-displaced lobsters tagged and returned to their point of capture, distance and angle travelled appears to be random with distance increasing as function of body size. However, for juvenile and subadult lobsters tagged and displaced away from their point of capture, the distance and angle travelled when released is significantly directed toward the point of capture. Thus, it appears that the map and compass ability of Caribbean spiny lobsters appears early in ontogeny and may allow for individuals to safely explore unfamiliar locations while retaining knowledge of how to return to known shelter. This ability to expand their known habitat map while maintaining knowledge of critical diurnal shelter locations is expected to facilitate their ontogenetic dispersal to adult habitat.

In situ customized apolipoprotein B48-enriched protein corona enhances oral gene delivery of chitosan-based nanoparticles

The formation of protein corona (PC) is important for promoting the in vivo delivery of nanoparticles (NPs). However, PC formed in the physiological environment of oral delivery is poorly understood. Here, we engineered seven types of trimethyl chitosan–cysteine (TC) NPs, with distinct molecular weights, quaternization degrees, and thiolation degrees, to deeply investigate the influence of various PC formed in the physiological environment of oral delivery on in vivo gene delivery of polymeric NPs, further constructing the relationship between the surface characteristics of NPs and the efficacy of oral gene delivery. Our findings reveal that TC7 NPs, with high molecular weight, moderate quaternization, and high sulfhydryl content, modulate PC formation in the gastrointestinal tract, thereby reducing particle size and promoting oral delivery of gene loaded TC7 NPs. Orally delivered TC7 NPs target macrophages by in situ adsorption of apolipoprotein (Apo) B48 in intestinal tissue, leading to the improved in vivo antihepatoma efficacy via the natural tumor homing ability of macrophages. Our results suggest that efficient oral delivery of genes can be achieved through an in situ customized ApoB48-enriched PC, offering a promising modality in treating macrophage-related diseases.

Initial orientation and homing performances in the lacertid lizard Podarcis siculus

Homing abilities of lizards after experimental dislocations have been found to be well developed in several species. Following our preliminary findings in Podarcis siculus, the present paper reports a new series of experiments on homing performances and initial orientation behaviour upon release. For this purpose, three series of releases were performed at increasing distances from the home areas in which the lizards were captured (range 85–245 m). In each series, two groups of lizards were released: the route-based visual cues during displacement were denied to one of them (NVIS), but allowed for the other (YVIS). The results of initial orientation showed that both are significantly homeward oriented at all three distances tested. Male and female YVIS and female NVIS are similarly homeward oriented, while the male NVIS are not. All 74 lizards successfully returned to their respective home areas. Eleven lizards homed on the same day they were released, while most of them homed during the 1st day after release (n = 51) and the rest on the 2nd day (n = 12). The different transport treatments did not influence homing success at the different distances tested. These results seem to support the use of a geocentric pilotage strategy to re-enter home from the release spot. Alternatively, the possibility that P. siculus use a sun compass and a mosaic map to find their way home is also discussed.