Laminin 411 acts as a potent inducer of umbilical cord mesenchymal stem cell differentiation into insulin-producing cells

Abstract

BackgroundDiabetes mellitus (DM) is an incurable metabolic disease constituting a major threat to human health. Insulin-producing cells (IPCs) differentiated from mesenchymal stem cells (MSCs) hold great promise in the treatment of DM. The development of an efficient IPC induction system is a crucial step for the clinical application of IPCs for DM. Laminin 411 is a key component of the basement membrane and is involved in the regulation of cell differentiation; however, little is known about a role of laminin 411 in the regulation of IPC differentiation from human MSCs.MethodsMSCs were isolated from human umbilical cord (UC-MSCs) and expanded in an in vitro culture system. UC-MSCs were then cultured in the IPC induction and differentiation medium in the presence of laminin 411. Flow cytometry, Quantitative realtime PCR, immunofluorescence staining, ELISA, Western blotting and other techniques were applied to determine IPC generation, insulin expression and related mechanisms. To evaluate potential therapeutic efficacy of IPCs induced from UC-MSCs, a type-1 diabetes (T1DM) rat model was generated using streptozotocin. Blood glucose, insulin levels, and survival of rats were monitored periodically following intravenous injection of the tested cells.ResultsLaminin 411 markedly induced the expression of the genes Foxa2 and Sox17, markers for pancreatic precursor cells, efficiently induced IPC differentiation from MSCs, and up-regulated insulin expression at both mRNA and protein levels. Furthermore, the expression of the genes known to govern insulin expression including Pdx1 and Ngn3 was markedly induced by laminin 411, which suggests that Pdx1 and Ngn3 signaling pathways are involved in laminin 411 induced-insulin expression machinery. More importantly, administration of laminin 411-induced IPCs rapidly and significantly down-regulated fasting blood glucose levels, significantly reduced the HbA1c concentration and markedly improved the symptoms and survival of T1DM rats.ConclusionsOur results demonstrate that laminin 411 acts as a potent differentiation inducer of IPCs from UC-MSCs via the Pdx1 and Ngn3 signaling pathways. Moreover, transfusion of laminin 411 induced-IPCs more efficiently improves symptoms and survival of T1DM rats. These novel finding highlights a potential clinical application of laminin 411 induced-IPCs in the treatment of T1DM, which calls for further studies.

Optimization of cell growth on palmitoyl‐hyaluronan knitted scaffolds developed for tissue engineering applications

“…These possible mechanisms are in concordance with the MSC‐UBC ability to adhere only on MGEL‐scaffold which is stabilized by crosslinking. MGEL is also known to support MSC proliferation, while LAM is known inducer of MSC differentiation generally accompanied by the drop in metabolic rate …”

“…MGEL is also known to support MSC proliferation, 51 while LAM is known inducer of MSC differentiation generally accompanied by the drop in metabolic rate. 52 ADSC adhesion on FNC-treated palmHA scaffold MSCs from adipose tissue represent an attractive type of multipotent adult stem cells because of their noncontroversial source, relative abundance, ease of isolation, and expandability. Adipose stem cells (ADSC) are nowadays used in various TE applications, 53 including cardiac regeneration.…”

Regeneration of Pulp/Dentin-Like Tissue in Immature Necrotic Permanent Dog Teeth Using Adipose Tissue-Derived Mesenchymal Stem Cells

“…Cells were then incubated with an antimouse immunoglobulin G fluorescein-conjugated secondary antibody (Millipore Corp, Temecula, CA, USA) for 45 min on ice, after which the cell suspensions were washed twice and analyzed using the FACS Calibur flow cytometry system using CXP Software version 2.2. (BD Biosciences NJ, USA) [27].…”

The Making of Pancreatic β Cells: Advances and Apprehensions

“…Intriguingly, the insulin levels secreted by these cells in response to glucose challenge have varied. Exendine-4 (EX-4) [131] and Laminin 411 [132] could also be used to optimally differentiate the adipose-derived mesenchymal cells (ADMSCs) and umbilical cord MSCs, respectively, into insulin producing cells. The conversion of δ cells into β cells also is an age-dependent process [133].…”