Promise(s) of Mesenchymal Stem Cells as an In Vitro Model System to Depict Pre-Diabetic/Diabetic Milieu in WNIN/GR-Ob Mutant Rats

Madhira, Soundarya Lakshmi; Challa, S. S.; Chalasani, Maniprabha; Nappanveethl, Giridharan; Bhonde, Ramesh; Ajumeera, Rajanna; Venkatesan, Vijayalakshmi

doi:10.1371/journal.pone.0048061

Cited by 29 publications

(23 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Il-1b have been previously shown to induce TNF expression in endocrine cells (a and b cells) via calcineurin/nuclear factor of activated T cells (NFAT) and MAPK Signaling. 38 Furthermore, our earlier reports on adipose tissue 39 and mesenchymal stem cells (bone marrow) 40 have substantiated inflammation to play a central role in obesity with IR in WNIN mutant rat. We also found increased CD11b positive cells (macrophage marker) localized in islets as compared to lean littermates and controls.…”

Section: E998099-6mentioning

confidence: 81%

Islet adaptation to obesity and insulin resistance in WNIN/GR-Ob rats

Singh¹,

Ganneru²,

Malakapalli³

et al. 2014

Islets

Self Cite

View full text Add to dashboard Cite

WNIN/GR-Ob mutant rat is a novel animal model to study metabolic syndrome (obesity, insulin resistance, hyperinsulinemia, impaired glucose tolerance and cardiovascular diseases). We have investigated the islet characteristics of obese mutants at different age groups (1, 6 and 12 months) to assess the islet changes in response to early and chronic metabolic stress. Our data demonstrates altered islet cell morphology and function (hypertrophy, fibrotic lesions, vacuolation, decreased stimulation index, increased TNFa, ROS and TBARS levels) in mutants as compared to controls. Furthermore, network analysis (gene-gene interaction) studied in pancreas demonstrated increased inflammation as a key factor underlying obesity/metabolic syndrome in mutants. These observations pave way to explore this model to understand islet adaptation in response to metabolic syndrome.

show abstract

Section: E998099-6mentioning

confidence: 81%

Islet adaptation to obesity and insulin resistance in WNIN/GR-Ob rats

Singh¹,

Ganneru²,

Malakapalli³

et al. 2014

Islets

Self Cite

View full text Add to dashboard Cite

show abstract

“…In establishing a suitable cell source for systemic immunotherapy, understanding of the trophic and immunomodulatory properties of the MSC source is central. Long-term exposure to the diabetic environment has been suggested to induce disease memory in BM-MSCs [37], characterized by an increased expression of proinflammatory markers such as IL-6. Although our mRNA expression data supports a fourfold increase of IL-6 in LT1D MSCs compared with HCs, baseline secretion of IL-6 protein, along with PGE2, CXCL1, CXCL6, and IDO activity, were not significantly changed in the diabetes MSCs.…”

Section: Discussionmentioning

confidence: 99%

Type 1 Diabetes Mellitus Donor Mesenchymal Stromal Cells Exhibit Comparable Potency to Healthy Controls In Vitro

Davies

Alm

Heldring

et al. 2016

Stem Cells Translational Medicine

View full text Add to dashboard Cite

Bone marrow mesenchymal stromal cells (BM-MSCs) have been characterized and used in many clinical studies based on their immunomodulatory and regenerative properties. We have recently reported the benefit of autologous MSC systemic therapy in the treatment of type 1 diabetes mellitus (T1D). Compared with allogeneic cells, use of autologous products reduces the risk of eliciting undesired complications in the recipient, including rejection, immunization, and transmission of viruses and prions; however, comparable potency of autologous cells is required for this treatment approach to remain feasible. To date, no analysis has been reported that phenotypically and functionally characterizes MSCs derived from newly diagnosed and late-stage T1D donors in vitro with respect to their suitability for systemic immunotherapy. In this study, we used gene array in combination with functional in vitro assays to address these questions. MSCs from T1D donors and healthy controls were expanded from BM aspirates. BM mononuclear cell counts and growth kinetics were comparable between the groups, with equivalent colony-forming unit-fibroblast capacity. Gene microarrays demonstrated differential gene expression between healthy and late-stage T1D donors in relation to cytokine secretion, immunomodulatory activity, and wound healing potential. Despite transcriptional differences, T1D MSCs did not demonstrate a significant difference from healthy controls in immunosuppressive activity, migratory capacity, or hemocompatibility. We conclude that despite differential gene expression, expanded MSCs from T1D donors are phenotypically and functionally similar to healthy control MSCs with regard to their immunomodulatory and migratory potential, indicating their suitability for use in autologous systemic therapy. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1485-1495 SIGNIFICANCEThe potential for mesenchymal stromal cells (MSCs) as a cell-based therapy in the treatment of immunologic disorders has been well established. Recent studies reported the clinical potential for autologous MSCs as a systemic therapy in the treatment of type I diabetes mellitus (T1D). The current study compared the genotypic and phenotypic profiles of bone marrow-derived MSCs from T1D and healthy donors as autologous (compared with allogeneic) therapy provides distinct advantages, such as reduced risk of immune reaction and transmission of infectious agents. The findings of the current study demonstrate that despite moderate differences in T1D MSCs at the gene level, these cells can be expanded in culture to an extent corresponding to that of MSCs derived from healthy donors. No functional difference in terms of immunosuppressive activity, blood compatibility, or migratory capacity was evident between the groups. The study findings also show that autologous MSC therapy holds promise as a T1D treatment and should be evaluated further in clinical trials.

show abstract

“…22 Supporting findings from insulinoma 22 and primary islet cells 22 also demonstrate diverse UPR genes upregulation as the probable factors for pancreatic β-cell dysregulation, 22 in agreement with our present data. The impetus using this animal model where we had looked in to Primary islet cell cultures 23 and Islet cell aggregates (ICAs) generated in vitro from BM-MSCs from these mutants unequivocally showed that islets/ICAs were non responsive to glucose challenge 8 when compared with controls, further suggests for β-cell dysfunctions in mutants (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…Pancreatic tissues were collected under sterile conditions in RNAlater (Qiagen). Total RNA was isolated as per the methods of Madhira et al 8 and purified using a Qiagen RNeasy mini kit (74104, Qiagen). RNA integrity was assessed by Agilent bioanalyzer 2100 and visualized using the 18S and 28S ribosomal bands on agarose gel.…”

Section: Resultsmentioning

confidence: 99%