Adult bone marrow-derived cells trans-differentiating into insulin-producing cells for the treatment of type I diabetes

Oh, Seh–Hoon; Muzzonigro, Toni M; Bae, Seog Nyeon; Laplante, Jennifer; Hatch, Heather; Petersen, Bryon E.

doi:10.1038/labinvest.3700074

Cited by 245 publications

(190 citation statements)

References 40 publications

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“…Because the phenomenon occurs in both type 1 and type 2 models, and can be duplicated by glucose injections in mice, hyperglycemia appears to trigger its occurrence. This interpretation is supported by the observation that Ϸ50% of unfractionated BMDC start transcribing insulin within days of incubation in high-glucose medium (7).…”

mentioning

confidence: 75%

Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes

Fujimiya

Kojima

Ichinose³

et al. 2007

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

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We previously reported that diabetes in mice is associated with the appearance of proinsulin-producing (Proins-P) cells in the liver. It was unclear, however, whether these Proins-P bone marrowderived cells (BMDC) merely transit through the liver or undergo fusion with hepatocytes, normally an extremely rare event. In this study, we found that, in diabetes, BMDC in the liver produce not only Proins but also TNF-␣, suggesting that diabetes reprograms gene expression in BMDC, turning on ''inappropriate'' genes. Bone marrow transplantation using genetically marked donor and recipient mice showed that fusion occurs between Proins-P BMDC and hepatocytes. Cell fusion is further supported by the presence of the Y chromosome in Proins-P cells in female mice that received male bone marrow transplantation cells. Morphologically, Proins-P fusion cells are albumin-producing hepatocytes that constitute Ϸ2.5% of the liver section area 5 months after diabetes induction. An extensive search failed to reveal any fusion cells in nondiabetic mice. Thus, diabetes causes fusion between Proins-P BMDC and hepatocytes in vivo, an observation that has implications for the pathophysiology of diabetes as well as the fundamental biology of heterotypic cell fusion.cell fusion ͉ diabetes mellitus ͉ diabetic complications ͉ liver R ecent reports from different laboratories document that bone marrow-derived cells (BMDC) can fuse with hepatocytes in vivo, and such fusion events can contribute to liver regeneration (1-4). However, with the exception of unique genetic models, e.g., fumarylacetoacetate hydrolase (Fah)-deficient mice (1, 2), in which wild-type BMDC confer a marked growth advantage, BMDC-hepatocyte fusion appears to be extremely rare. In a review article, Thorgeirsson and Grisham (5) estimated that transplanted BMDC generate hepatocyte-like cells in the liver at a frequency of Յ10 O4 . In fact, the yield of presumed BMDC-hepatocyte fusion cells ranges from 0 to Ͻ0.05% in Ͼ80% of reports published before August 2005 (5). Apart from the rarity of the event, there is little information on whether BMDC-hepatocyte cell fusion is regulated by physiological body functions, and whether it is affected by pathological conditions other than the extreme example of Fah-deficient mice that received bone marrow transplantation (BMT) from Fahexpressing mice.Our laboratory recently reported the appearance of proinsulin-producing (Proins-P) cells in the bone marrow of diabetic rats and mice (6). The Proins-P BMDC migrate out of the bone marrow and populate different organs and tissues, including liver and fat. Because the phenomenon occurs in both type 1 and type 2 models, and can be duplicated by glucose injections in mice, hyperglycemia appears to trigger its occurrence. This interpretation is supported by the observation that Ϸ50% of unfractionated BMDC start transcribing insulin within days of incubation in high-glucose medium (7).Diabetes mellitus is a prevalent disease that affects Ϸ7% of the U.S. population and a rapidly growing proportion o...

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mentioning

confidence: 75%

Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes

Fujimiya

Kojima

Ichinose³

et al. 2007

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

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“…40,41 Since BM contains heterogenous populations of TCSC, our data explain, without invoking the concept of HSC plasticity, why several investigators were able to demonstrate in vitro cultures the appearance of skeletal muscle, liver, pancreatic or neural cells growing from plated BM-, mPB-or CB-derived cells. 43,[63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82] Separation of BM-derived HSC from TCSC Since both HSC and TCSC express CXCR4, it was obvious that by employing chemotactic isolation to an SDF-1 gradient, we will isolate from BMMNC both CXCR4 þ HSC and nonhematopoietic stem cells. Thus to separate both of these populations of stem cells, we stained them with antibodies against panhematopoietic antigen CD45 and subsequently sorted CD45 þ and CD45 À cells by FACS (Figure 3).…”

Section: Bm Stem Cells Are Heterogeneousmentioning

confidence: 99%

Bone marrow as a home of heterogenous populations of nonhematopoietic stem cells

et al. 2005

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Evidence is presented that bone marrow (BM) in addition to CD45 positive hematopoietic stem cells contains a rare population of heterogenous CD45 negative nonhematopoietic tissue committed stem cells (TCSC). These nonhematopoietic TCSC (i) are enriched in population of CXCR4 þ CD34 þ AC133 þ lin À CD45 À and CXCR4 þ Sca-1 þ lin À CD45 À in humans and mice, respectively, (ii) display several markers of pluripotent stem cells (PSC) and (iii) as we envision are deposited in BM early in development. Thus, since BM contains versatile nonhematopoietic stem cells, previous studies on plasticity trans-dedifferentiation of BM-derived hematopoietic stem cells (HSC) that did not include proper controls to exclude this possibility could lead to wrong interpretations. Therefore, in this spotlight review we present this alternative explanation of 'plasticity' of BMderived stem cells based on the assumption that BM stem cells are heterogenous. We also discuss a potential relationship of TCSC/PSC identified by us with other BM-derived CD45 negative nonhematopoietic stem cells that were recently identified by other investigators (eg MSC, MAPC, USSC and MIAMI cells). Finally, we discuss perspectives and pitfalls in potential application of these cells in regenerative medicine.

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“…One strategy (1)(2)(3)(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.…”

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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Adult bone marrow-derived cells trans-differentiating into insulin-producing cells for the treatment of type I diabetes

Cited by 245 publications

References 40 publications

Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes

Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes

Bone marrow as a home of heterogenous populations of nonhematopoietic stem cells

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

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