scholarly journals Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Lucas H. Armitage ◽  
Scott E. Stimpson ◽  
Katherine E. Santostefano ◽  
Lina Sui ◽  
Similoluwa Ogundare ◽  
...  
Keyword(s):  
T Cells ◽  
Pluripotent Stem Cells ◽  
Cell Interactions ◽  
Proof Of Concept ◽  
Β Cells ◽  
Single Donor ◽  
Induced Pluripotent ◽  
Cell Cell

Type 1 diabetes (T1D) is a disease that arises due to complex immunogenetic mechanisms. Key cell-cell interactions involved in the pathogenesis of T1D are activation of autoreactive T cells by dendritic cells (DC), migration of T cells across endothelial cells (EC) lining capillary walls into the islets of Langerhans, interaction of T cells with macrophages in the islets, and killing of β-cells by autoreactive CD8+ T cells. Overall, pathogenic cell-cell interactions are likely regulated by the individual’s collection of genetic T1D-risk variants. To accurately model the role of genetics, it is essential to build systems to interrogate single candidate genes in isolation during the interactions of cells that are essential for disease development. However, obtaining single-donor matched cells relevant to T1D is a challenge. Sourcing these genetic variants from human induced pluripotent stem cells (iPSC) avoids this limitation. Herein, we have differentiated iPSC from one donor into DC, macrophages, EC, and β-cells. Additionally, we also engineered T cell avatars from the same donor to provide an in vitro platform to study genetic influences on these critical cellular interactions. This proof of concept demonstrates the ability to derive an isogenic system from a single donor to study these relevant cell-cell interactions. Our system constitutes an interdisciplinary approach with a controlled environment that provides a proof-of-concept for future studies to determine the role of disease alleles (e.g. IFIH1, PTPN22, SH2B3, TYK2) in regulating cell-cell interactions and cell-specific contributions to the pathogenesis of T1D.

scholarly journals Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes

2021 ◽  
Author(s):  
Lucas H Armitage ◽  
Scott E Stimpson ◽  
Katherin E Santostefano ◽  
Lina Sui ◽  
Similoluwa O Ogundare ◽  
...  
Keyword(s):  
T Cells ◽  
Pluripotent Stem Cells ◽  
Cell Interactions ◽  
Proof Of Concept ◽  
Β Cells ◽  
Single Donor ◽  
Induced Pluripotent ◽  
Cell Cell

Type 1 diabetes is a disease that arises due to complex immunogenetic mechanisms. Key cell-cell interactions involved in the pathogenesis of T1D are activation of autoreactive T cells by dendritic cells (DC), migration of T cells across endothelial cells (EC) lining capillary walls into the islets of Langerhans, interaction of T cells with macrophages in the islets, and killing of β-cells by autoreactive CD8+ T cells. Overall, pathogenic cell-cell interactions are likely regulated by the individual's collection of genetic T1D-risk variants. To accurately model the role of genetics, it is essential to build systems to interrogate single candidate genes in isolation during the interactions of cells that are essential for disease development. However, obtaining single-donor matched cells relevant to T1D is a challenge. Sourcing these genetic variants from human induced pluripotent stem cells (iPSC) avoids this limitation. Herein, we have differentiated iPSC from one donor into DC, macrophages, EC, and β-cells. Additionally, we also engineered T cell avatars from the same donor to provide an in vitro platform to study genetic influences on these critical cellular interactions. This proof of concept demonstrates the ability to derive an isogenic system from a single donor to study these relevant cell-cell interactions. Our system constitutes an interdisciplinary approach with a controlled environment that provides a proof-of-concept for future studies to determine the role of disease alleles (e.g. IFIH1, PTPN22, SH2B3, TYK2) in regulating cell-cell interactions and cell-specific contributions to the pathogenesis of T1D.

scholarly journals Neuronal Cell Sheets of Cortical Motor Neuron Phenotype Derived from Human iPSCs

2017 ◽  
Vol 26 (8) ◽  
pp. 1355-1364 ◽  
Author(s):  
Noboru Suzuki ◽  
Nagisa Arimitsu ◽  
Jun Shimizu ◽  
Kenji Takai ◽  
Chieko Hirotsu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Zinc Finger ◽  
Motor Neurons ◽  
Pluripotent Stem Cells ◽  
Neuronal Cell ◽  
Cell Interactions ◽  
Cell Sheets ◽  
Cortical Motor ◽  
Induced Pluripotent ◽  
Cell Cell

Transplantation of stem cells that differentiate into more mature neural cells brings about functional improvement in preclinical studies of stroke. Previous transplant approaches in the diseased brain utilized injection of the cells in a cell suspension. In addition, neural stem cells were preferentially used for grafting. However, these cells had no specific relationship to the damaged tissue of stroke and brain injury patients. The injection of cells in a suspension destroyed the cell–cell interactions that are suggested to be important for promoting functional integrity of cortical motor neurons. In order to obtain suitable cell types for grafting in patients with stroke and brain damage, a protocol was modified for differentiating human induced pluripotent stem cells from cells phenotypically related to cortical motor neurons. Moreover, cell sheet technology was applied to neural cell transplantation, as maintaining the cell–cell communications is regarded important for the repair of host brain architecture. Accordingly, neuronal cell sheets that were positive Forebrain Embryonic Zinc Finger (Fez) family zinc finger 2 (FEZF2), COUP-TF-interacting protein 2, insulin-like growth factor–binding protein 4 (IGFBP4), cysteine-rich motor neuron 1 protein precursor (CRIM1), and forkhead box p2 (FOXP2) were developed. These markers are associated with cortical motoneurons that are appropriate for the transplant location in the lesions. The sheets allowed preservation of cell–cell interactions shown by synapsin1 staining after transplantation to damaged mouse brains. The sheet transplantation brought about partial structural restoration and the improvement of motor functions in hemiplegic mice. Collectively, the novel neuronal cell sheets were transplanted into damaged motor cortices; the cell sheets maintained cell–cell interactions and improved the motor functions in the hemiplegic model mice. The motoneuron cell sheets are possibly applicable for stroke patients and patients with brain damage by using patient-specific induced pluripotent stem cells.

scholarly journals NK Cells and Type 1 Diabetes

2006 ◽  
Vol 13 (2-4) ◽  
pp. 101-107 ◽  
Author(s):  
Melanie Rodacki ◽  
Adolpho Milech ◽  
José Egídio Paulo de Oliveira
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Nk Cells ◽  
Target Cells ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Immune Mediated ◽  
Antigen Presenting

Type 1 diabetes (T1D) is characterized by an immuno-mediated progressive destruction of the pancreatic β cells. Due to the ability of NK cells to kill target cells as well as to interact with antigen-presenting and T cells, it has been suggested that they could be involved in one or multiple steps of the immune-mediated attack that leads to T1D. Abnormalities in the frequency and activity of NK cells have been described both in animal models and patients with T1D. Some of these alterations are linked to its onset while others seem to be a consequence of the disease. Here, we discuss the main characteristics of NK cells and review the studies that investigated the role of NK cells in T1D, both in mouse models and humans.

scholarly journals Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jinxiu Rui ◽  
Songyan Deng ◽  
Ana Luisa Perdigoto ◽  
Gerald Ponath ◽  
Romy Kursawe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Type 1 Diabetes ◽  
Immune Cells ◽  
Autoimmune Diabetes ◽  
Bone Marrow Transplants ◽  
Β Cells ◽  
Inflammatory Genes

Abstractβ cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO β cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between β cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in β cells may reduce activating pathologic immune cells and killing of β cells.

The Role of Human T-Lymphotropic Virus Type 1 (HTLV-1)-Infected Dendritic Cells in the Development of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

1999 ◽  
Vol 73 (6) ◽  
pp. 4575-4581 ◽  
Author(s):  
Masahiko Makino ◽  
Satoshi Shimokubo ◽  
Shin-Ichi Wakamatsu ◽  
Shuji Izumo ◽  
Masanori Baba
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Virus Type ◽  
Spastic Paraparesis ◽  
Tropical Spastic Paraparesis ◽  
Normal Donor ◽  
Dependent Manner ◽  
T Lymphotropic Virus

ABSTRACT The development of human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is closely associated with the activation of T cells which are HTLV-1 specific but may cross-react with neural antigens (Ags). Immature dendritic cells (DCs), differentiated from normal donor monocytes by using recombinant granulocyte-macrophage colony-stimulating factor and recombinant interleukin-4, were pulsed with HTLV-1 in vitro. The pulsed DCs contained HTLV-1 proviral DNA and expressed HTLV-1 Gag Ag on their surface 6 days after infection. The DCs matured by lipopolysaccharides stimulated autologous CD4+ T cells and CD8+ T cells in a viral dose-dependent manner. However, the proliferation level of CD4+ T cells was five- to sixfold higher than that of CD8+ T cells. In contrast to virus-infected DCs, DCs pulsed with heat-inactivated virions activated only CD4+ T cells. To clarify the role of DCs in HAM/TSP development, monocytes from patients were cultured for 4 days in the presence of the cytokines. The expression of CD86 Ag on DCs was higher and that of CD1a Ag was more down-regulated than in DCs generated from normal monocytes. DCs from two of five patients expressed HTLV-1 Gag Ag. Furthermore, both CD4+ and CD8+ T cells from the patients were greatly stimulated by contact with autologous DCs pulsed with inactivated viral Ag as well as HTLV-1-infected DCs. These results suggest that DCs are susceptible to HTLV-1 infection and that their cognate interaction with T cells may contribute to the development of HAM/TSP.

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