<i>In Vitro</i> Differentiation of Human Placenta-derived Adherent Cells into Insulin-producing Cells

Sun, NZ; Ji, HS

doi:10.1177/147323000903700215

Cited by 22 publications

(9 citation statements)

References 16 publications

(7 reference statements)

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“…It controls the maturation of pancreatic islet cells by regulating insulin 1 and other down stream genes. It was shown that the expression of PDX-1 is switched on first followed by other IPCs-related genes (41). Ngn3 appears transiently during the development of the pancreas.…”

Section: Discussionmentioning

confidence: 99%

Insulin-Producing Cells from Adult Human Bone Marrow Mesenchymal Stem Cells Control Streptozotocin-Induced Diabetes in Nude Mice

et al. 2013

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Harvesting, expansion and directed differentiation of human bone marrow-derived mesenchymal stem cells (BM-MSCs) could provide an autologous source of surrogate β-cells that would alleviate the limitations of availability and/or allogenic rejection following pancreatic or islet transplantation. Bone marrow cells were obtained from three adult type 2 diabetic volunteers and 3 non-diabetic donors. After 3 days in culture, adherent MSCs were expanded for 2 passages. At passage 3, differentiation was carried out in a 3-staged procedure. Cells were cultured in a glucose-rich medium containing several activation and growth factors. Cells were evaluated in-vitro by flow cytometry, immunolabelling, Rt-PCR and human insulin and c-peptide release in responses to increasing glucose concentrations. One thousand cell-clusters were inserted under the renal capsule of diabetic nude mice followed by monitoring of their diabetic status. At the end of differentiation, ~5–10% of cells were immunofluorescent for insulin, c-peptide or glucagon; insulin and c-peptide were co-expressed. Nanogold immunolabelling for electron microscopy demonstrated the presence of c-peptide in the rough endoplasmic reticulum. Insulin-producing cells (IPCs) expressed transcription factors and genes of pancreatic hormones similar to those expressed by pancreatic islets. There was a stepwise increase in human insulin and c-peptide release by IPCs in response to increasing glucose concentrations. Transplantation of IPCs into nude diabetic mice resulted in control of their diabetic status for 3 months. The sera of IPC-transplanted mice contained human insulin and c-peptide but negligible levels of mouse insulin. When the IPCs-bearing kidneys were removed, rapid return of diabetic state was noted. BM-MSCs from diabetic and non-diabetic human subjects could be differentiated without genetic manipulation to form IPCs which, when transplanted, could maintain euglycaemia in diabetic mice for 3 months. Optimization of the culture conditions are required to improve the yield of IPCs and their functional performance.

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Section: Discussionmentioning

confidence: 99%

Insulin-Producing Cells from Adult Human Bone Marrow Mesenchymal Stem Cells Control Streptozotocin-Induced Diabetes in Nude Mice

et al. 2013

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“…PDX-1 controls the maturation of pancreatic islet cells by regulating insulin 1 and other downstream genes. It was shown that the expression of PDX-1 is switched on first followed by other IPCs-related genes [18]. In the current study, we have utilized Cnp in the one-step protocol, TSA in the two-step protocol, and β -mercaptoethanol in the three-step protocol to induce expression of PDX-1.…”

Section: Discussionmentioning

confidence: 99%

Generation of Insulin-Producing Cells from Human Bone Marrow-Derived Mesenchymal Stem Cells: Comparison of Three Differentiation Protocols

Gabr

Zakaria

Refaie

et al. 2014

BioMed Research International

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Introduction. Many protocols were utilized for directed differentiation of mesenchymal stem cells (MSCs) to form insulin-producing cells (IPCs). We compared the relative efficiency of three differentiation protocols. Methods. Human bone marrow-derived MSCs (HBM-MSCs) were obtained from three insulin-dependent type 2 diabetic patients. Differentiation into IPCs was carried out by three protocols: conophylline-based (one-step protocol), trichostatin-A-based (two-step protocol), and β-mercaptoethanol-based (three-step protocol). At the end of differentiation, cells were evaluated by immunolabeling for insulin production, expression of pancreatic endocrine genes, and release of insulin and c-peptide in response to increasing glucose concentrations. Results. By immunolabeling, the proportion of generated IPCs was modest (≃3%) in all the three protocols. All relevant pancreatic endocrine genes, insulin, glucagon, and somatostatin, were expressed. There was a stepwise increase in insulin and c-peptide release in response to glucose challenge, but the released amounts were low when compared with those of pancreatic islets. Conclusion. The yield of functional IPCs following directed differentiation of HBM-MSCs was modest and was comparable among the three tested protocols. Protocols for directed differentiation of MSCs need further optimization in order to be clinically meaningful. To this end, addition of an extracellular matrix and/or a suitable template should be attempted.

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“…A very recent report [153] has suggested the differentiability of placenta-derived adherent cells into insulin-producing cells. The authors demonstrated for the first time that differentiated placenta-derived cells expressed Pdx-1, Insulin and Glut 2 genes.…”

Section: Placenta Derived Stem Cellsmentioning

confidence: 98%

Wharton’s Jelly Mesenchymal Stem Cells as Candidates for Beta Cells Regeneration: Extending the Differentiative and Immunomodulatory Benefits of Adult Mesenchymal Stem Cells for the Treatment of Type 1 Diabetes

Anzalone

Iacono

Loria

et al. 2010

Stem Cell Rev and Rep

128

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Mesenchymal stem cells (MSC) are uniquely capable of crossing germinative layers borders (i.e. are able to differentiate towards ectoderm-, mesoderm- and endoderm-derived cytotypes) and are viewed as promising cells for regenerative medicine approaches in several diseases. Type I diabetes therapy should potentially benefit from such differentiated cells: the search for alternatives to organ/islet transplantation strategies via stem cells differentiation is an ongoing task, significant goals having been achieved in most experimental settings (e.g. insulin production and euglycaemia restoration), though caution is still needed to ensure safe and durable effects in vivo. MSC are obtainable in high numbers via ex vivo culture and can be differentiated towards insulin-producing cells (IPC). Moreover, recent reports evidenced that MSC possess immunomodulatory activities (acting on both innate and acquired immunity effectors) which should result in a reduction of the immunogenicity of transplanted cells, thus limiting rejection. Moreover it has been proposed that MSC administration should be used to attenuate the autoimmune processes which lead to the destruction of beta cells. This review illustrates the recent advances made in differentiating human MSC to IPC. In particular, we compare the effectiveness of the differentiation protocols applied, the markers and functional assays used to characterize differentiated progeny, and the in vivo controls. We further speculate on how MSC derived from Wharton's jelly of human umbilical cord may represent a more promising regenerative medicine tool, as recently demonstrated for endoderm-derived organs (as liver) in human subjects, also considering their peculiar immunomodulatory features compared to other MSC populations.

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In Vitro Differentiation of Human Placenta-derived Adherent Cells into Insulin-producing Cells

Cited by 22 publications

References 16 publications

Insulin-Producing Cells from Adult Human Bone Marrow Mesenchymal Stem Cells Control Streptozotocin-Induced Diabetes in Nude Mice

Insulin-Producing Cells from Adult Human Bone Marrow Mesenchymal Stem Cells Control Streptozotocin-Induced Diabetes in Nude Mice

Generation of Insulin-Producing Cells from Human Bone Marrow-Derived Mesenchymal Stem Cells: Comparison of Three Differentiation Protocols

Wharton’s Jelly Mesenchymal Stem Cells as Candidates for Beta Cells Regeneration: Extending the Differentiative and Immunomodulatory Benefits of Adult Mesenchymal Stem Cells for the Treatment of Type 1 Diabetes

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