scholarly journals Mesenchymal stromal cells improve human islet function through released products and extracellular matrix

2017 ◽  
Vol 131 (23) ◽  
pp. 2835-2845 ◽  
Author(s):  
Ahmed A. Arzouni ◽  
Andreia Vargas-Seymour ◽  
Chloe L. Rackham ◽  
Paramjeet Dhadda ◽  
Guo-Cai Huang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Human Islets ◽  
Human Islet ◽  
Human Mscs ◽  
Islet Function ◽  
Secretory Function ◽  
Beneficial Effects

Aims: The aims of the present study were (i) to determine whether the reported beneficial effects of mesenchymal stromal cells (MSCs) on mouse islet function extend to clinically relevant human tissues (islets and MSCs), enabling translation into improved protocols for clinical human islet transplantation; and (ii) to identify possible mechanisms through which human MSCs influence human islet function. Materials and methods: Human islets were co-cultured with human adipose tissue-derived MSCs (hASCs) or pre-treated with its products – extracellular matrix (ECM) and annexin A1 (ANXA1). Mouse islets were pre-treated with mouse MSC-derived ECM. Islet insulin secretory function was assessed in vitro by radioimmunoassay. Quantitative RT-PCR was used to screen human adipMSCs for potential ligands of human islet G-protein-coupled receptors. Results: We show that co-culture with hASCs improves human islet secretory function in vitro, as measured by glucose-stimulated insulin secretion, confirming previous reports using rodent tissues. Furthermore, we demonstrate that these beneficial effects on islet function can be partly attributed to the MSC-derived products ECM and ANXA1. Conclusions: Our results suggest that hASCs have the potential to improve the quality of human islets isolated for transplantation therapy of Type 1 diabetes. Furthermore, it may be possible to achieve improvements in human islet quality in a cell-free culture system by using the MSC-derived products ANXA1 and ECM.

scholarly journals Interleukin-22 reverses human islet dysfunction and apoptosis triggered by hyperglycemia and LIGHT

2018 ◽  
Vol 60 (3) ◽  
pp. 171-183
Author(s):  
Shadab Abadpour ◽  
Bente Halvorsen ◽  
Afaf Sahraoui ◽  
Olle Korsgren ◽  
Pål Aukrust ◽  
...  
Keyword(s):  
Islet Cells ◽  
Harmful Effect ◽  
Human Islets ◽  
Protective Role ◽  
Human Islet ◽  
Islet Function ◽  
Post Transplantation ◽  
Interleukin 22 ◽  
Glucose Stimulated Insulin Secretion

Interleukin (IL)-22 has recently been suggested as an anti-inflammatory cytokine that could protect the islet cells from inflammation- and glucose-induced toxicity. We have previously shown that the tumor necrosis factor family member, LIGHT, can impair human islet function at least partly via pro-apoptotic effects. Herein, we aimed to investigate the protective role of IL-22 on human islets exposed to the combination of hyperglycemia and LIGHT. First, we found upregulation of LIGHT receptors (LTβR and HVEM) in engrafted human islets exposed to hyperglycemia (>11 mM) for 17 days post transplantation by using a double islet transplantation mouse model as well as in human islets cultured with high glucose (HG) (20 mM glucose) + LIGHT in vitro, and this latter effect was attenuated by IL-22. The effect of HG + LIGHT impairing glucose-stimulated insulin secretion was reversed by IL-22. The harmful effect of HG + LIGHT on human islet function seemed to involve enhanced endoplasmic reticulum stress evidenced by upregulation of p-IRE1α and BiP, elevated secretion of pro-inflammatory cytokines (IL-6, IL-8, IP-10 and MCP-1) and the pro-coagulant mediator tissue factor (TF) release and apoptosis in human islets, whereas all these effects were at least partly reversed by IL-22. Our findings suggest that IL-22 could counteract the harmful effects of LIGHT/hyperglycemia on human islet cells and potentially support the strong protective effect of IL-22 on impaired islet function and survival.

scholarly journals Conditioned media from mesenchymal stromal cells restore sodium transport and preserve epithelial permeability in an in vitro model of acute alveolar injury

2014 ◽  
Vol 306 (11) ◽  
pp. L975-L985 ◽  
Author(s):  
Arnaud Goolaerts ◽  
Nadia Pellan-Randrianarison ◽  
Jérôme Larghero ◽  
Valérie Vanneaux ◽  
Yurdagül Uzunhan ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Sodium Transport ◽  
In Vitro Model ◽  
Prostaglandin E ◽  
Human Mscs ◽  
Epithelial Permeability ◽  
Alveolar Epithelial ◽  
Vitro Model

Mesenchymal stromal cells (MSCs) or their media (MSC-M) were reported to reverse acute lung injury (ALI)-induced decrease of alveolar fluid clearance. To determine the mechanisms by which MSC-M exert their beneficial effects, an in vitro model of alveolar epithelial injury was created by exposing primary rat alveolar epithelial cells (AECs) to hypoxia (3% O2) plus cytomix, a combination of IL-1β, TNF-α, and IFN-γ. MSC-M were collected from human MSCs exposed for 12 h to either normoxia (MSC-M) or to hypoxia plus cytomix (HCYT-MSC-M). This latter condition was used to model the effect of alveolar inflammation and hypoxia on paracrine secretion of MSCs in the injured lung. Comparison of paracrine soluble factors in MSC media showed that the IL-1 receptor antagonist and prostaglandin E2 were markedly increased while keratinocyte growth factor (KGF) was twofold lower in HCYT-MSC-M compared with MSC-M. In AECs, hypoxia plus cytomix increased protein permeability, reduced amiloride-sensitive short-circuit current (AS- Isc), and also decreased the number of α-epithelial sodium channel (α-ENaC) subunits in the apical membrane. To test the effects of MSC media, MSC-M and HCYT-MSC-M were added for an additional 12 h to AECs exposed to hypoxia plus cytomix. MSC-M and HCYT-MSC-M completely restored epithelial permeability to normal. MSC-M, but not HCYT-MSC-M, significantly prevented the hypoxia plus cytomix-induced decrease of ENaC activity and restored apical α-ENaC channels. Interestingly, KGF-deprived MSC-M were unable to restore amiloride-sensitive sodium transport, indicating a possible role for KGF in the beneficial effect of MSC-M. These results indicate that MSC-M may be a preferable therapeutic option for ALI.

The effect of extracellular matrix components on the preservation of human islet function in vitro

Biomaterials ◽  
2010 ◽  
Vol 31 (7) ◽  
pp. 1676-1682 ◽  
Author(s):  
Jamal Daoud ◽  
Maria Petropavlovskaia ◽  
Lawrence Rosenberg ◽  
Maryam Tabrizian
Keyword(s):  
Extracellular Matrix ◽  
Human Islet ◽  
Islet Function ◽  
Extracellular Matrix Components ◽  
Matrix Components

scholarly journals Nuclear shape, protrusive behaviour and in vivo retention of human bone marrow mesenchymal stromal cells is controlled by Lamin-A/C expression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yvonne L. Dorland ◽  
Anne S. Cornelissen ◽  
Carlijn Kuijk ◽  
Simon Tol ◽  
Mark Hoogenboezem ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Nuclear Lamina ◽  
Cell Types ◽  
Lamin A ◽  
Human Mscs ◽  
Hematopoietic Stem ◽  
Graft Versus Host

Abstract Culture expanded mesenchymal stromal cells (MSCs) are being extensively studied for therapeutic applications, including treatment of graft-versus-host disease, osteogenesis imperfecta and for enhancing engraftment of hematopoietic stem cells after transplantation. Thus far, clinical trials have shown that the therapeutic efficiency of MSCs is variable, which may in part be due to inefficient cell migration. Here we demonstrate that human MSCs display remarkable low migratory behaviour compared to other mesodermal-derived primary human cell types. We reveal that specifically in MSCs the nucleus is irregularly shaped and nuclear lamina are prone to wrinkling. In addition, we show that expression of Lamin A/C is relatively high in MSCs. We further demonstrate that in vitro MSC migration through confined pores is limited by their nuclei, a property that might correlate to the therapeutic inefficiency of administered MSC in vivo. Silencing expression of Lamin A/C in MSCs improves nuclear envelope morphology, promotes the protrusive activity of MSCs through confined pores and enhances their retention in the lung after intravenous administration in vivo. Our findings suggest that the intrinsic nuclear lamina properties of MSCs underlie their limited capacity to migrate, and that strategies that target the nuclear lamina might alter MSC-based cellular therapies.

scholarly journals Characterization of the Effects of Mesenchymal Stromal Cells on Mouse and Human Islet Function

2019 ◽  
Author(s):  
Ahmed A. Arzouni ◽  
Andreia Vargas‐Seymour ◽  
Paramjeet K. Dhadda ◽  
Chloe L. Rackham ◽  
Guo‐Cai Huang ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Human Islet ◽  
Islet Function

scholarly journals Use of adult mesenchymal stromal cells in tissue repair: impact of physical exercise

2019 ◽  
Vol 317 (4) ◽  
pp. C642-C654 ◽  
Author(s):  
Celine Bourzac ◽  
Morad Bensidhoum ◽  
Stephane Pallu ◽  
Hugues Portier
Keyword(s):  
Physical Exercise ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Tissue Repair ◽  
Mechanical Stimulus ◽  
Great Promise ◽  
Muscular Tissue ◽  
Beneficial Effects ◽  
Tissue Recovery

Physical exercise (PE) has unquestionable beneficial effects on health, which likely extend into several organ-to-cell physiological processes. At the cell scale, endogenous mesenchymal stromal cells (MSCs) contribute to tissue repair, although their repair capacities may be insufficient in paucicellular or severely damaged tissues. For this reason, MSC transplantation holds great promise for tissue repair. With the goals of understanding if PE has beneficial effects on MSC biology and if PE potentiates their role in tissue repair, we reviewed literature reports regarding the effects of PE on MSC properties (specifically, proliferation, differentiation, and homing) and of a combination of PE and MSC transplantation on tissue repair (specifically neural, cartilage, and muscular tissues). Contradictory results have been reported; interpretation is complicated because various and different species, cell sources, and experimental protocols, specifically exercise programs, have been used. On the basis of these data, the effects of exercise on MSC proliferation and differentiation depend on exercise characteristics (type, intensity, duration, etc.) and on the characteristics of the tissue from which the MSCs were collected. For the in vitro studies, the level of strain (and other details of the mechanical stimulus), the time elapsed between the end of exposure to strain and MSC collection, the age of the donors, as well as the passage number at which the MSCs are evaluated also play a role. The combination of PE and MSC engraftment improves neural, cartilage, and muscular tissue recovery, but it is not clear whether the effects of MSCs and exercise are additive or synergistic.

Human marrow-derived mesenchymal stromal cells decrease cisplatin renotoxicity in vitro and in vivo and enhance survival of mice post-intraperitoneal injection

2010 ◽  
Vol 299 (6) ◽  
pp. F1288-F1298 ◽  
Author(s):  
Nicoletta Eliopoulos ◽  
Jing Zhao ◽  
Manaf Bouchentouf ◽  
Kathy Forner ◽  
Elena Birman ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Human Kidney ◽  
Chemotherapeutic Agents ◽  
Human Mscs ◽  
Proliferating Cells ◽  
Phosphorylated Akt

Acute kidney injury (AKI) can occur from the toxic side-effects of chemotherapeutic agents such as cisplatin. Bone marrow-derived mesenchymal stromal cells (MSCs) have demonstrated wide therapeutic potential often due to beneficial factors they secrete. The goal of this investigation was to evaluate in vitro the effect of human MSCs (hMSCs) secretome on cisplatin-treated human kidney cells, and in vivo the consequence of hMSCs intraperitoneal (ip) implantation in mice with AKI. Our results revealed that hMSCs-conditioned media improved survival of HK-2 human proximal tubular cells exposed to cisplatin in vitro. This enhanced survival was linked to increased expression of phosphorylated Akt (Ser473) and was reduced by a VEGF-neutralizing antibody. In vivo testing of these hMSCs established that ip administration in NOD-SCID mice decreased cisplatin-induced kidney function impairment, as demonstrated by lower blood urea nitrogen levels and higher survival. In addition, blood phosphorous and amylase levels were also significantly decreased. Moreover, hMSCs reduced the plasma levels of several inflammatory cytokines/chemokines. Immunohistochemical examination of kidneys showed less apoptotic and more proliferating cells. Furthermore, PCR indicated the presence of hMSCs in mouse kidneys, which also showed enhanced expression of phosphorylated Akt. In conclusion, our study reveals that hMSCs can exert prosurvival effects on renal cells in vitro and in vivo, suggests a paracrine contribution for kidney protective abilities of hMSCs delivered ip, and supports their clinical potential in AKI.

Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1549-1553 ◽  
Author(s):  
Karin Tarte ◽  
Julien Gaillard ◽  
Jean-Jacques Lataillade ◽  
Loic Fouillard ◽  
Martine Becker ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Calf Serum ◽  
Human Leukocyte ◽  
Culture Conditions ◽  
Human Mscs ◽  
Clinical Grade ◽  
Human Mesenchymal Stromal Cells

Abstract Clinical-grade human mesenchymal stromal cells (MSCs) have been expanded in vitro for tissue engineering or immunoregulatory purposes without standardized culture conditions or release criteria. Although human MSCs show poor susceptibility for oncogenic transformation, 2 recent studies described their capacity to accumulate chromosomal instability and to give rise to carcinoma in immunocompromised mice after long-term culture. We thus investigated the immunologic and genetic features of MSCs expanded with fetal calf serum and fibroblast growth factor or with platelet lysate in 4 cell-therapy facilities during 2 multicenter clinical trials. Cultured MSCs showed a moderate expression of human leukocyte antigen-DR without alteration of their low immunogenicity or their immunomodulatory capacity. Moreover, some transient and donor-dependent recurring aneuploidy was detected in vitro, independently of the culture process. However, MSCs with or without chromosomal alterations showed progressive growth arrest and entered senescence without evidence of transformation either in vitro or in vivo.

Human multipotent mesenchymal stromal cells inhibit proliferation of PBMCs independently of IFNγR1 signaling and IDO expression

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 2197-2200 ◽  
Author(s):  
Friederike Gieseke ◽  
Burkhardt Schütt ◽  
Susanne Viebahn ◽  
Ewa Koscielniak ◽  
Wilhelm Friedrich ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Binding Proteins ◽  
Multipotent Mesenchymal Stromal Cells ◽  
Human Mscs ◽  
Igf Binding Proteins ◽  
Peripheral Blood Mononuclear ◽  
Tryptophan Degradation ◽  
Igf Binding

Abstract Multipotent mesenchymal stromal cells (MSCs) inhibit proliferation, helper, and effector functions in most if not all peripheral blood mononuclear cell (PBMC) subpopulations in vitro. The molecular mechanism is widely thought to imply tryptophan degradation by the interferon-γ (IFNγ)–induced expression of indoleamine 2,3-dioxygenase (IDO). However, IDO inhibitors were not able to restore proliferation of PBMCs in each case. Moreover, human MSCs with an IFNγ receptor 1 (R1) defect inhibited proliferation of HLA-mismatched PBMCs to a similar extent as control MSCs. In contrast to healthy MSCs, IFNγR1-deficient MSCs showed no detectable mRNA for IDO—neither in the absence nor in the presence of recombinant human IFNγ, nor in coculture with HLA-mismatched PBMCs. Based on gene expression profiling, we were able to show that insulin-like growth factor (IGF)–binding proteins contribute to the inhibitory mechanism of MSCs. Taken together, human MSCs exert important immunomodulatory functions in the absence of IFNγR1 signaling and IDO, partially accounted for by IGF-binding proteins.

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