We have identified, cultured, characterized, and propagated adult pluripotent stem cells (PSC) from a subset of human peripheral blood monocytes. These cells, which in appearance resemble fibroblasts, expand in the presence of macrophage colony-stimulating factor and display monocytic and hematopoietic stem cell markers including CD14, CD34, and CD45. We have induced these cells to differentiate into mature macrophages by lipopolysaccharide, T lymphocytes by IL-2, epithelial cells by epidermal growth factor, endothelial cells by vascular endothelial cell growth factor, neuronal cells by nerve growth factor, and liver cells by hepatocyte growth factor. The pluripotent nature of individual PSC was further confirmed by a clonal analysis. The ability to store, expand, and differentiate these PSC from autologous peripheral blood should make them valuable candidates for transplantation therapy. P luripotent stem cells (PSC) are a valuable resource for research, drug discovery, and transplantation (1, 2). These cells or their mature progeny can be used to study differentiation processes, identify and test lineage-specific drugs, or replace tissues damaged by a disease. However, the use of PSC from human fetuses, umbilical cords, or embryonic tissues derived from in vitro fertilized eggs raises ethical and legal questions, poses a risk of transmitting infections, and͞or may be ineffective because of immune rejection. A way to circumvent these problems is by exploiting autologous stem cells, preferably from an accessible tissue. In this context, it has been reported that bone marrow contains cells that appear to have the ability to transdifferentiate into mature cells belonging to distinct cell lineages (2). A recent study indicated that bone marrow mesenchymal PSC can be expanded in vitro and after transplantation differentiate in vivo into cells belonging to distinct lineages (3). Other studies have, however, raised the possibility that such mature cells may result from fusion of stem cells with mature resident tissue cells (4,5).In the present studies, we have described the characterization and expansion in vitro of a yet unidentified subset of human peripheral blood monocytes that behave as PSC. We have shown that these cells can be induced to acquire macrophage, lymphocyte, epithelial, endothelial, neuronal, and hepatocyte phenotypes in the absence of a fusion with preexisting mature tissue cells. The ability to obtain these PSC from an easily accessible source such as peripheral blood and to store them in liquid nitrogen should make them valuable candidates for autologous transplantation. Materials and MethodsCell Culture. Monocytes were obtained from buffy coats (each from 500 ml of peripheral blood) of healthy individuals (LifeSource Blood Services, Glenview, IL) by using a selective attachment procedure as described (6, 7). Fresh mononuclear cells for this procedure and͞or after storage in liquid nitrogen in FBS (Harlan Breeders, Indianapolis) containing 10% dimethyl sulfoxide (Sigma) were obtained after Ficoll-...
BackgroundInability to control autoimmunity is the primary barrier to developing a cure for type 1 diabetes (T1D). Evidence that human cord blood-derived multipotent stem cells (CB-SCs) can control autoimmune responses by altering regulatory T cells (Tregs) and human islet β cell-specific T cell clones offers promise for a new approach to overcome the autoimmunity underlying T1D.MethodsWe developed a procedure for Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates lymphocytes from the whole blood and briefly co-cultures them with adherent CB-SCs before returning them to the patient's circulation. In an open-label, phase1/phase 2 study, patients (n = 15) with T1D received one treatment with the Stem Cell Educator. Median age was 29 years (range: 15 to 41), and median diabetic history was 8 years (range: 1 to 21).ResultsStem Cell Educator therapy was well tolerated in all participants with minimal pain from two venipunctures and no adverse events. Stem Cell Educator therapy can markedly improve C-peptide levels, reduce the median glycated hemoglobin A1C (HbA1C) values, and decrease the median daily dose of insulin in patients with some residual β cell function (n = 6) and patients with no residual pancreatic islet β cell function (n = 6). Treatment also produced an increase in basal and glucose-stimulated C-peptide levels through 40 weeks. However, participants in the Control Group (n = 3) did not exhibit significant change at any follow-up. Individuals who received Stem Cell Educator therapy exhibited increased expression of co-stimulating molecules (specifically, CD28 and ICOS), increases in the number of CD4+CD25+Foxp3+ Tregs, and restoration of Th1/Th2/Th3 cytokine balance.ConclusionsStem Cell Educator therapy is safe, and in individuals with moderate or severe T1D, a single treatment produces lasting improvement in metabolic control. Initial results indicate Stem Cell Educator therapy reverses autoimmunity and promotes regeneration of islet β cells. Successful immune modulation by CB-SCs and the resulting clinical improvement in patient status may have important implications for other autoimmune and inflammation-related diseases without the safety and ethical concerns associated with conventional stem cell-based approaches.Trial registrationClinicalTrials.gov number, NCT01350219.
Although neurons attract the most attention in neurobiology, our current knowledge of neural circuit can only partially explain the neurological and psychiatric conditions of the brain. Thus, it is also important to consider the influence of brain interstitial system (ISS), which refers to the space among neural cells and capillaries. The ISS is the major compartment of the brain microenvironment that provides the immediate accommodation space for neural cells, and it occupies 15% to 20% of the total brain volume. The brain ISS is a dynamic and complex space connecting the vascular system and neural networks and it plays crucial roles in substance transport and signal transmission among neurons. Investigation of the brain ISS can provide new perspectives for understanding brain architecture and function and for exploring new strategies to treat brain disorders. This review discussed the anatomy of the brain ISS under both physiological and pathological conditions, biophysical modeling of the brain ISS and in vivo measurement and imaging techniques, including recent findings on brain ISS divisions. Moreover, the implications of ISS knowledge for basic neuroscience and clinical applications are addressed.
Summary Regulatory CD4+ CD25+ T (Treg) cells with the ability to suppress host immune responses against self‐ or non‐self antigens play important roles in the processes of autoimmunity, transplant rejection, infectious diseases and cancers. The proper regulation of CD4+ CD25+ Treg cells is thus critical for optimal immune responses. Toll‐like receptor (TLR)‐mediated recognition of specific structures of invading pathogens initiates innate as well as adaptive immune responses via antigen‐presenting cells (APCs). Interestingly, new evidence suggests that TLR signalling may directly or indirectly regulate the immunosuppressive function of CD4+ CD25+ Treg cells in immune responses. TLR signalling may shift the balance between CD4+ T‐helper cells and Treg cells, and subsequently influence the outcome of the immune response. This immunomodulation pathway may therefore have potential applications in the treatment of graft rejection, autoimmune diseases, infection diseases and cancers.
Angiotensin-converting enzyme-2 (ACE2) has been recognized as the binding receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Flow cytometry demonstrated that there was little to no expression of ACE2 on most of the human peripheral blood-derived immune cells including CD4 + T, CD8 + T, activated CD4 + / CD8 + T, Tregs, Th17, NKT, B, NK cells, monocytes, dendritic cells, and granulocytes.There was no ACE2 expression on platelets and very low level of ACE2 protein expression on the surface of human primary pulmonary alveolar epithelial cells. The ACE2 expression was markedly upregulated on the activated type 1 macrophages (M1).Immunohistochemistry demonstrated high expressions of ACE2 on human tissue macrophages, such as alveolar macrophages, Kupffer cells within livers, and microglial cells in brain at steady state. The data suggest that alveolar macrophages, as the frontline immune cells, may be directly targeted by the SARS-CoV-2 infection and therefore need to be considered for the prevention and treatment of COVID-19.
CD4(+)CD25(+) regulatory T cells (Treg cells) are an important subset of T cells for keeping proper immune responses and tolerance. However, the effects of gamma radiation on CD4(+)CD25(high) Foxp3(+) Treg cells have not been examined previously. In the present study, we compared the sensitivity of mouse CD4(+)CD25(high) Foxp3(+) Treg cells and CD4(+)CD25(-) T cells to gamma radiation in vitro and in vivo. After C57BL/6 mice received a whole-body dose of 5 Gy gamma rays, the numbers of lymphocyte subsets in blood, lymph nodes, spleens and thymuses clearly decreased. However, gamma radiation significantly enhanced the ratios of CD4(+)CD25(high) Treg cells and CD4(+)CD25(high) Foxp3(+) Treg cells to CD4(+) T cells in the blood, lymph nodes, spleens and thymuses of mice. More dead cells were observed in CD4(+)CD25(-) T cells than in CD4(+)CD25(high) Treg cells or CD4(+)CD25(high) Foxp3(+) Treg cells when the cells were irradiated in vitro, indicating that CD4(+)CD25(high) Foxp3(+) Treg cells are more resistant to gamma radiation than other T cells. Moreover, a higher expression of Bcl-2 in CD4(+)CD25(high) Treg cells was detected compared with that in CD4(+)CD25(-) T cells. CD4(+)CD25(+) Treg cells from irradiated mice were functional, though their immunosuppressive ability was somewhat impaired compared to those from nonirradiated mice as determined by an in vitro assay. These results indicate that mouse CD4(+)CD25(+) Treg cells and CD4(+)CD25(-) T effector cells have different sensitivities to gamma radiation in mice.
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