Reversal of established autoimmune diabetes by restoration of endogenous β cell function

Ryu, Shinichiro; Kodama, Shohta; Ryu, Kazuko; Schoenfeld, David; Faustman, Denise L.

doi:10.1172/jci12335

Cited by 163 publications

(100 citation statements)

References 44 publications

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“…The β cell number increases dramatically in the first year of rodent life [12,26], up to 10-fold in cases of insulin resistance [27], and up to 1.5-fold during pregnancy [28,29]. Recent experiments suggest that when not hindered by persistent autoimmune attack or the toxicity of high blood glucose levels [30], β cells have the capacity to regenerate. While the mechanism regulating β cell expansion remains unclear, our findings indicate that all β cells are capable of replication and are therefore viable targets for in vitro or in vivo expansion.…”

Section: Discussionmentioning

confidence: 99%

All β Cells Contribute Equally to Islet Growth and Maintenance

2007

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In healthy adult mice, the β cell population is not maintained by stem cells but instead by the replication of differentiated β cells. It is not known, however, whether all β cells contribute equally to growth and maintenance, as it may be that some cells replicate while others do not. Understanding precisely which cells are responsible for β cell replication will inform attempts to expand β cells in vitro, a potential source for cell replacement therapy to treat diabetes. Two experiments were performed to address this issue. First, the level of fluorescence generated by a pulse of histone 2B–green fluorescent protein (H2BGFP) expression was followed over time to determine how this marker is diluted with cell division; a uniform loss of label across the entire β cell population was observed. Second, clonal analysis of dividing β cells was completed; all clones were of comparable size. These results support the conclusion that the β cell pool is homogeneous with respect to replicative capacity and suggest that all β cells are candidates for in vitro expansion. Given similar observations in the hepatocyte population, we speculate that for tissues lacking an adult stem cell, they are replenished equally by replication of all differentiated cells.

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Section: Discussionmentioning

confidence: 99%

All β Cells Contribute Equally to Islet Growth and Maintenance

2007

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“…3a), then rested them overnight before counting. We added rapamycin (until day 7) because it selectively expands the highest number of T regs with greatest capacity for suppressing CD8+ cells40414243. This process successfully produced CD4+CD25 hi T regs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Homogeneous Expansion of Human T-Regulatory Cells Via Tumor Necrosis Factor Receptor 2

Okubo

Mera

Wang

et al. 2013

Sci Rep

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149

183

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T-regulatory cells (Tregs) are a rare lymphocyte subtype that shows promise for treating infectious disease, allergy, graft-versus-host disease, autoimmunity, and asthma. Clinical applications of Tregs have not been fully realized because standard methods of expansion ex vivo produce heterogeneous progeny consisting of mixed populations of CD4 + T cells. Heterogeneous progeny are risky for human clinical trials and face significant regulatory hurdles. With the goal of producing homogeneous Tregs, we developed a novel expansion protocol targeting tumor necrosis factor receptors (TNFR) on Tregs. In in vitro studies, a TNFR2 agonist was found superior to standard methods in proliferating human Tregs into a phenotypically homogeneous population consisting of 14 cell surface markers. The TNFR2 agonist-expanded Tregs also were functionally superior in suppressing a key Treg target cell, cytotoxic T-lymphocytes. Targeting the TNFR2 receptor during ex vivo expansion is a new means for producing homogeneous and potent human Tregs for clinical opportunities.

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“…Harvesting splenic cells from a healthy donor animal and injecting them into a diabetic recipient with advanced TID is an effective therapy for two reasons. The freshly harvested and matched donor splenocytes are administered with a second treatment (an inducer of the cytokine Tumor Necrosis Factor) that halted autoimmune attack by destroying the host’s rare autoreactive lymphocytes responsible for killing islet cells (Ryu et al, 2001;Kodamaet al, 2003). The matched splenocytes directly and indirectly contributed to regeneration of pancreatic islets and return of blood glucose levels to normal (Ryu et al, 2001; Kodama et al, 2003; Yin et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…While most splenic cells bear the cell surface marker for lymphoid cells, CD45+, the splenocytes contributing to islet regeneration bore no such markings, rendering them CD45−. Using two types of lineage tracing techniques, the donor CD45− splenocytes were found to have differentiated into islet cells in the recipient (Ryu et al, 2001; Kodama et al, 2003). Only the CD45− cells were found to have contributed to regenerating islets.…”

Section: Introductionmentioning

confidence: 99%

“…The two diseases in the NOD mouse share overlapping pathology as a result of similar genetic and protein abnormalities (Hayashi and Faustman, 1999, 2000). Further, the salivary glands and the pancreas are developmentally related: they derive from the same embryonic region that spawns the spleen (Lonyai et al, 2008b; Kodama et al, 2003, 2005a,b; Robertson et al, 2008; Park et al, 2009; Yin et al, 2006; Ryu et al, 2001; Nishio et al, 2006; Suri et al, 2006). In animals with Sjogren’s syndrome, donor splenocytes both directly and indirectly regenerate the salivary glands (Tran et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Stem cells in the spleen: Therapeutic potential for Sjogren's syndrome, type I diabetes, and other disorders

Faustman

Davis

2010

The International Journal of Biochemistry & Cell Biology

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The view of the spleen as an unnecessary organ has been shattered. The evidence shows the spleen to be a source of naturally-occurring multipotent stem cells with possibly pluripotent potential. The stem cells are sequestered in the spleen of not only of animals but also of normal human adults. The reservoir of cells is set for differentiation and they need not be manipulated in vitro or ex vivo before autologous or heterologous use. Splenic stem cells, of Hox11 lineage, have been found in disease or injury to differentiate into pancreatic islets, salivary epithelial cells and osteoblast-like cells, cranial neurons, cochlea, lymphocytes, and more differentiated immune cells that repair injured heart cells. Injury or disease in target tissues induces these stem cells, still in the spleen, to upregulate the same embryonic transcription factors artificially introduced into induced pluripotent stem cells (iPS). Splenic stem cells may have broad pluripotent potential, but unlike iPS cells, possess low oncogenic risk.

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Reversal of established autoimmune diabetes by restoration of endogenous β cell function

Cited by 163 publications

References 44 publications

All β Cells Contribute Equally to Islet Growth and Maintenance

All β Cells Contribute Equally to Islet Growth and Maintenance

Homogeneous Expansion of Human T-Regulatory Cells Via Tumor Necrosis Factor Receptor 2

Stem cells in the spleen: Therapeutic potential for Sjogren's syndrome, type I diabetes, and other disorders

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