RESUMO
Spinal cord injury results in locomotor impairment attributable to the formation of an inhibitory fibrous scar, which prevents axonal regeneration after trauma. The scarcity of knowledge about the molecular and cellular mechanisms involved in scar formation after spinal cord lesion impede the design of effective therapies. Recent studies, by using state-of-the-art technologies, including genetic tracking and blockage of pericytes in combination with optogenetics, reveal that pericyte blockage facilitates axonal regeneration and neuronal integration into the local neural circuitry. Strikingly, a pericyte subset is essential during scarring after spinal cord injury, and its arrest results in motor performance improvement. The arising knowledge from current research will contribute to novel approaches to develop therapies for spinal cord injury. We review novel advances in our understanding of pericyte biology in the spinal cord.
Assuntos
Neurônios/metabolismo , Pericitos/metabolismo , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Animais , Cicatriz/metabolismo , Cicatriz/patologia , Humanos , Neurônios/patologia , Pericitos/patologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologiaRESUMO
Dermal wound healing is the process of repairing and remodeling skin following injury. Delayed or aberrant cutaneous healing poses a challenge for the health care system. The lack of detailed understanding of cellular and molecular mechanisms involved in this process hampers the development of effective targeted treatments. In a recent study, Parfejevs et al.-using state-of-the-art technologies, including in vivo sophisticated Cre/loxP techniques in combination with a mouse model of excisional cutaneous wounding-reveal that Schwann cells induce adult dermal wound healing. Strikingly, genetic ablation of Schwann cells delays wound contraction and closure, decreases myofibroblast formation, and impairs skin re-epithelization after injury. From a drug development perspective, Schwann cells are a new cellular candidate to be activated to accelerate skin healing. Here, we summarize and evaluate recent advances in the understanding of Schwann cells roles in the skin microenvironment.
Assuntos
Células de Schwann/fisiologia , Pele/lesões , Cicatrização/fisiologia , Ferimentos e Lesões/patologia , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Camundongos , Receptor Cross-Talk , Pele/patologiaRESUMO
The premetastatic niche formed by primary tumor-derived molecules contributes to fixation of cancer metastasis. The design of efficient therapies is limited by the current lack of knowledge about the details of cellular and molecular mechanisms involved in the premetastatic niche formation. Recently, the role of pericytes in the premetastatic niche formation and lung metastatic tropism was explored by using state-of-the-art techniques, including in vivo lineage-tracing and mice with pericyte-specific KLF4 deletion. Strikingly, genetic inactivation of KLF4 in pericytes inhibits pulmonary pericyte expansion and decreases metastasis in the lung. Here, we summarize and evaluate recent advances in the understanding of pericyte contribution to premetastatic niche formation. Cancer Res; 78(11); 2779-86. ©2018 AACR.
Assuntos
Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Pericitos/patologia , Animais , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologiaRESUMO
Glioblastoma is the most common malignant brain cancer in adults, with poor prognosis. The blood-brain barrier limits the arrival of several promising anti-glioblastoma drugs, and restricts the design of efficient therapies. Recently, by using state-of-the-art technologies, including thymidine kinase targeting system in combination with glioblastoma xenograft mouse models, it was revealed that targeting glioblastoma-derived pericytes improves chemotherapy efficiency. Strikingly, ibrutinib treatment enhances chemotherapeutic effectiveness, by targeting pericytes, improving blood-brain barrier permeability, and prolonging survival. This study identifies glioblastoma-derived pericyte as a novel target in the brain tumor microenvironment during carcinogenesis. Here, we summarize and evaluate recent advances in the understanding of pericyte's role in the glioblastoma microenvironment.
Assuntos
Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/tratamento farmacológico , Pericitos/metabolismo , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Animais , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Camundongos , Pericitos/patologia , Piperidinas , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Adipocyte infiltration in the bone marrow follows chemotherapy or irradiation. Previous studies indicate that bone marrow fat cells inhibit hematopoietic stem cell function. Recently, Zhou et al. (2017) using state-of-the-art techniques, including sophisticated Cre/loxP technologies, confocal microscopy, in vivo lineage-tracing, flow cytometry, and bone marrow transplantation, reveal that adipocytes promote hematopoietic recovery after irradiation. This study challenges the current view of adipocytes as negative regulators of the hematopoietic stem cells niche, and reopens the discussion about adipocytes' roles in the bone marrow. Strikingly, genetic deletion of stem cell factor specifically from adipocytes leads to deficiency in hematopoietic stem cells, and reduces animal survival after myeloablation, The emerging knowledge from this research will be important for the treatment of multiple hematologic disorders. © 2017 International Society for Advancement of Cytometry.
Assuntos
Adipócitos/fisiologia , Células da Medula Óssea/fisiologia , Transplante de Medula Óssea , Adipócitos/transplante , Animais , Medula Óssea/fisiologia , Transplante de Medula Óssea/tendências , Células-Tronco Hematopoéticas/fisiologia , HumanosRESUMO
Bone marrow fibrosis is a reactive process, and a central pathological feature of primary myelofibrosis. Revealing the origin of fibroblastic cells in the bone marrow is crucial, as these cells are considered an ideal, and essential target for anti-fibrotic therapy. In 2 recent studies, Decker et al. (2017) and Schneider et al. (2017), by using state-of-the-art techniques including in vivo lineage-tracing, provide evidence that leptin receptor (LepR)-expressing and Gli1-expressing cells are responsible for fibrotic tissue deposition in the bone marrow. However, what is the relationship between these 2 bone marrow cell populations, and what are their relative contributions to bone marrow fibrosis remain unclear. From a drug development perspective, these works bring new cellular targets for bone marrow fibrosis.
Assuntos
Células da Medula Óssea/patologia , Medula Óssea/patologia , Fibroblastos/patologia , Mielofibrose Primária/metabolismo , Receptores para Leptina/metabolismo , Animais , Dissidências e Disputas , HumanosRESUMO
Bone marrow fibrosis is a critical component of primary myelofibrosis in which normal bone marrow tissue and blood-forming cells are gradually replaced with scar tissue. The specific cellular and molecular mechanisms that cause bone marrow fibrosis are not understood. A recent study using state-of-the-art techniques, including in vivo lineage tracing, provides evidence that Gli1+ cells are the cells responsible for fibrotic disease in the bone marrow. Strikingly, genetic depletion of Gli1+ cells rescues bone marrow failure and abolishes myelofibrosis. This work introduces a new central cellular target for bone marrow fibrosis. The knowledge that emerges from this research will be important for the treatment of several malignant and nonmalignant disorders.