Reversal of experimental diabetes by multiple bone marrow transplantation

Banerjee, Meenal; Kumar, Ashok; Bhonde, Ramesh

doi:10.1016/j.bbrc.2004.12.176

Cited by 83 publications

(68 citation statements)

References 31 publications

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“…In an interesting study, Kojima et al showed that extrapancreatic proinsulinpositive cells were present in liver, adipose tissue, and bone marrow of diabetic rats [18]. Transplantation of genetically marked bone marrow cells in diabetic rats showed hyperglycemia-induced proinsulin expression in bone marrow cells.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells Derived from Bone Marrow of Diabetic Patients Portrait Unique Markers Influenced by the Diabetic Microenvironment

Phadnis¹,

Ghaskadbi²,

Hardikar³

et al. 2009

Rev Diabet Stud

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■ AbstractCellular microenvironment is known to play a critical role in the maintenance of human bone marrow-derived mesenchymal stem cells (BM-MSCs). It was uncertain whether BM-MSCs obtained from a 'diabetic milieu' (dBM-MSCs) offer the same regenerative potential as those obtained from healthy (non-diabetic) individuals (hBM-MSCs). To investigate the effect of diabetic microenvironment on human BMMSCs, we isolated and characterized these cells from diabetic patients (dBM-MSCs). We found that dBM-MSCs expressed mesenchymal markers such as vimentin, smooth muscle actin, nestin, fibronectin, CD29, CD44, CD73, CD90, and CD105. These cells also exhibited multilineage differentiation potential, as evident from the generation of adipocytes, osteocytes, and chondrocytes when exposed to lineage specific differentiation media. Although the cells were similar to hBM-MSCs, 6% (3/54) of dBM-MSCs expressed proinsulin/C-peptide. Emanating from the diabetic microenvironmental milieu, we analyzed whether in vitro reprogramming could afford the maturation of the islet-like clusters (ICAs) derived from dBM-MSCs. Upon mimicking the diabetic hyperglycemic niche and the supplementation of fetal pancreatic extract, to differentiate dBM-MSCs into pancreatic lineage in vitro, we observed rapid differentiation and maturation of dBM-MSCs into islet-like cell aggregates. Thus, our study demonstrated that diabetic hyperglycemic microenvironmental milieu plays a major role in inducing the differentiation of human BM-MSCs in vivo and in vitro.

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Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells Derived from Bone Marrow of Diabetic Patients Portrait Unique Markers Influenced by the Diabetic Microenvironment

Phadnis¹,

Ghaskadbi²,

Hardikar³

et al. 2009

Rev Diabet Stud

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“…There also was attenuation of glomerular hypertrophy and tubular dilatation, but engraftment of the cells was not assayed. In additional experiments, multiple infusions of unfractionated marrow cells into mice with STZ-induced diabetes lowered blood sugar and improved the histomorphology of the pancreas (11). In experiments in which NOD mice were used as a model for type 1 diabetes, transplantation of wild-type bone marrow lowered blood sugar if the transplant was performed before, but not after, the onset of hyperglycemia (12).…”

mentioning

confidence: 99%

Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/ scid mice

Lee

Seo

Reger

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

670

556

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We tested the hypothesis that multipotent stromal cells from human bone marrow (hMSCs) can provide a potential therapy for human diabetes mellitus. Severe but nonlethal hyperglycemia was produced in NOD͞scid mice with daily low doses of streptozotocin on days 1-4, and hMSCs were delivered via intracardiac infusion on days 10 and 17. The hMSCs lowered blood glucose levels in the diabetic mice on day 32 relative to untreated controls (18.34 mM ؎ 1.12 SE vs. 27.78 mM ؎ 2.45 SE, P ‫؍‬ 0.0019). ELISAs demonstrated that blood levels of mouse insulin were higher in the hMSC-treated as compared with untreated diabetic mice, but human insulin was not detected. PCR assays detected human Alu sequences in DNA in pancreas and kidney on day 17 or 32 but not in other tissues, except heart, into which the cells were infused. In the hMSC-treated diabetic mice, there was an increase in pancreatic islets and ␤ cells producing mouse insulin. Rare islets contained human cells that colabeled for human insulin or PDX-1. Most of the ␤ cells in the islets were mouse cells that expressed mouse insulin. In kidneys of hMSC-treated diabetic mice, human cells were found in the glomeruli. There was a decrease in mesangial thickening and a decrease in macrophage infiltration. A few of the human cells appeared to differentiate into glomerular endothelial cells. Therefore, the results raised the possibility that hMSCs may be useful in enhancing insulin secretion and perhaps improving the renal lesions that develop in patients with diabetes mellitus.insulin ͉ pancreas ͉ streptozotocin ͉ transplantation P revious publications presented conflicting observations as to whether cells from bone marrow can provide a potential therapy for diabetes mellitus. One strategy (1-4) was to differentiate plastic adherent marrow cells in culture into insulin-secreting cells. A second strategy was to transplant diabetic mice with genetically labeled marrow and to search for labeled insulinproducing cells in the recipient mice. One study using a CRELoxP-GFP system found that 1.7-3% of the cells in islets of the recipient mice were marrow-derived and that GFP-labeled donor cells isolated from the islets expressed insulin, glucose transporter 2, and transcription factors typically found in ␤ cells (5). Three subsequent reports in which mice were transplanted with GFPexpressing bone marrow did not find evidence of marrow cells becoming insulin-producing cells in the pancreas of recipient mice (6-8), but in the reports it was difficult to exclude the possibility that the GFP gene was inactivated or that GFP-labeled cells were destroyed as they engrafted into islets. A third strategy was to determine whether systemically administered marrow cells enhanced regeneration of pancreatic insulin-producing cells in diabetic models. Hess et al. (9) reported that in NOD͞scid mice in which diabetes was induced with streptozotocin (STZ), partial marrow ablation followed by transplantation of either GFP-labeled whole-marrow or GFP-labeled c-kit ϩ cells from murine marrowenhanced r...

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“…Third, the therapeutic efficacy of the two subsets attributes clear advantage of the Fr25lin − cells in stabilization of glucose levels through sustained increase in insulin levels. In contrast, R/O progenitors and whole BMC grafts share limited capacity to elevate insulin levels, corroborating the partial and transient reduction in blood glucose levels mediated by hematopoietic progenitors (6,7,14,18,27,39,41,47,56).…”

Section: Discussionmentioning

confidence: 64%

“…In variance, hematopoietic progenitors and their progeny are found in the vasculature, ductal walls, and at islet perimeter, sustaining bright GFP signals. The activities of these cells are largely supportive of islet remodeling, including neovascularization (8,19,39,44,47,64), immunomodulation (6,7,12,39,42), stabilization of the stroma (7,40), and provision of cytokines (1,27). Third, the therapeutic efficacy of the two subsets attributes clear advantage of the Fr25lin − cells in stabilization of glucose levels through sustained increase in insulin levels.…”

Section: Discussionmentioning

confidence: 99%

“…The characteristics of differentiating Fr25lin − cells in the injured islets include upregulation of PDX-1, downregulation of tacking markers such as GFP, production of proinsulin, and secretion of insulin. Since Fr25lin − cells represent a small fraction of nucleated BMCs, the numbers of candidate stem cells might be insufficient in wBMC grafts used for hematopoietic reconstitution (6)(7)(8)14,19,22,39,40,47). However, transplantation of large BMC numbers, containing equivalent fractions of the elutriated Fr25lin − subset, resulted in undetectable morphological and functional incorporation in the islets.…”

Section: Discussionmentioning

confidence: 99%

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Two Distinct Mechanisms Mediate the Involvement of Bone Marrow Cells in Islet Remodeling: Neogenesis of Insulin-Producing Cells and Support of Islet Recovery

et al. 2015

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We have recently reported that small-sized bone marrow cells (BMCs) isolated by counterflow centrifugal elutriation and depleted of lineage markers (Fr25lin − ) have the capacity to differentiate and contribute to regeneration of injured islets. In this study, we assess some of the characteristics of these cells compared to elutriated hematopoietic progenitors (R/O) and whole BMCs in a murine model of streptozotocin-induced chemical diabetes. The GFP bright CD45+ progeny of whole BMCs and R/O progenitors progressively infiltrate the pancreas with evolution of donor chimerism; are found at islet perimeter, vascular, and ductal walls; and have a modest impact on islet recovery from injury. In contrast, Fr25lin− cells incorporate in the islets, convert to GFP dim CD45 − PDX-1 + phenotypes, produce proinsulin, and secrete insulin with significant contribution to stabilization of glucose homeostasis. The elutriated Fr25lin − cells express low levels of CD45 and are negative for SCA-1 and c-kit, as removal of cells expressing these markers did not impair conversion to produce insulin. BMCs mediate two synergistic mechanisms that contribute to islet recovery from injury: support of islet remodeling by hematopoietic cells and neogenesis of insulin-producing cells from stem cells.

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Reversal of experimental diabetes by multiple bone marrow transplantation

Cited by 83 publications

References 31 publications

Mesenchymal Stem Cells Derived from Bone Marrow of Diabetic Patients Portrait Unique Markers Influenced by the Diabetic Microenvironment

Mesenchymal Stem Cells Derived from Bone Marrow of Diabetic Patients Portrait Unique Markers Influenced by the Diabetic Microenvironment

Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/ scid mice

Two Distinct Mechanisms Mediate the Involvement of Bone Marrow Cells in Islet Remodeling: Neogenesis of Insulin-Producing Cells and Support of Islet Recovery

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