Mesenchymal stem cell-based therapy as a new therapeutic approach for acute inflammation.

Acute inflammatory diseases such as acute colitis, kidney injury, liver failure, lung injury, myocardial infarction, pancreatitis, septic shock, and spinal cord injury are significant causes of death worldwide. Despite advances in the understanding of its pathophysiology, there are many restrictions in the treatment of these diseases, and new therapeutic approaches are required. Mesenchymal stem cell-based therapy due to immunomodulatory and regenerative properties is a promising candidate for acute inflammatory disease management. Based on preclinical results, mesenchymal stem cells and their-derived secretome improved immunological and clinical parameters. Furthermore, many clinical trials of acute kidney, liver, lung, myocardial, and spinal cord injury have yielded promising results. In this review, we try to provide a comprehensive view of mesenchymal stem cell-based therapy in acute inflammatory diseases as a new treatment approach.

Human Bone Marrow Mesenchymal Stromal Cells Attenuate Tissue Injury and Reduce Inflammation in Experimental Acute Pancreatitis.

Purpose: Acute pancreatitis (AP) which is distinguished by local pancreatic necrosis, followingby systemic organ failure is known as an inflammatory disease. Up to now, there are only a fewtreatment options accessible for patients suffering from AP. In this study, we aimed to examinethe anti-inflammatory capacities of human bone marrow-derived mesenchymal stromal cells(hBM-MSCs) in a detailed AP model experiment. Methods: AP was induced in C57BL/6 mice by intraperitoneal administration of cerulein (100µg/kg/h × 7 doses) at intervals of 1 hour. Then, 2×105 MSCs were infused in the AP mice bytail vein 6 hours after the last cerulein injection. Mice were sacrificed 12 hours following theinjection of hBM-MSC, and blood samples and pancreas tissues were obtained. Results: We first determined the presence of transplanted hBM-MSC in the pancreas of micewith AP, but not the control mice. Our data indicate that administration of hBM-MSCs to micewith AP lead to (i) decreased serum levels of amylase, lipase and myeloperoxidase activities, (ii)downregulation of proinflammatory cytokine, macrophage inflammatory protein 2 (MIP-2), and(iii) upregulation of the anti-inflammatory cytokine, interleukin 10 (IL-10). Moreover, hBM-MSCadministration results in notably attenuated cerulein-induced histopathological alternationsand edema. Conclusion: we demonstrate that hBM-MSC attenuates AP signs and indicating that hMB-MSCtherapy could be a suitable approach for the treatment of inflammatory disease such as AP.

Effect of Hypoxia Preconditioned Adipose-Derived Mesenchymal Stem Cell Conditioned Medium on Cerulein-Induced Acute Pancreatitis in Mice.

Purpose: Acute pancreatitis (AP) is an inflammatory disorder distinguished by tissue injury and inflammation of the pancreas. Using paracrine potential of mesenchymal stem cells (MSCs) provides a useful clinical approach in treating inflammatory diseases. We investigated the therapeutic effects of adipose-derived MSC conditioned medium (CM) and hypoxia preconditioned adipose-derived MSC conditioned medium (HCM) in cerulein-induced AP in mice. Methods: AP was induced in C57BL/6 mice by intraperitoneal injection of cerulein (75 µg/ kg/h × 7 times). One hour following the last injection of cerulein, mice were treated with intraperitoneal injection of CM and HCM (500 µL/mice/30 min × 3 times). Twelve hours following the treatment, serum levels of amylase and lipase were measured. In addition, pancreas pathological changes, immunohistochemical examinations for evaluation of IL-6 expression and pancreatic myeloperoxidase (MPO) enzyme activity were analyzed. Results: The in vitro results of the morphological, differentiation and immunophenotyping analyses confirmed that hypoxia preconditioned MSCs (HP-MSCs) conserve MSCs characteristics after preconditioning. However, HP-MSCs significantly expressed high mRNA level of hypoxia inducible factor 1-α and higher level of total protein. The in vivo findings of the current study showed that CM and HCM significantly reduced the amylase & lipase activity, the severity of pancreas tissue injury and the expression of IL-6 and MPO enzyme activity compared with the AP group. However, no significant difference between CM and HCM groups was demonstrated. Conclusion: Use of CM and HCM can attenuate cerulein-induced AP and decrease inflammation in the pancreas tissue in AP mice.

Hydrogen Peroxide Preconditioning Promotes Protective Effects of Umbilical Cord Vein Mesenchymal Stem Cells in Experimental Pulmonary Fibrosis.

Purpose: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder with few available treatments. Mesenchymal stem cell therapy (MSCT), an innovative approach, has high therapeutic potential when used to treat IPF. According to recent data, preconditioning of MSCs can improve their therapeutic effects. Our research focuses on investigating the anti-inflammatory and antifibrotic effects of H2 O2 -preconditioned MSCs (p-MSCs) on mice with bleomycin-induced pulmonary fibrosis (PF). Methods: Eight-week-old male C57BL/6 mice were induced with PF by intratracheal (IT) instillation of bleomycin (4 U/kg). Human umbilical cord vein-derived MSCs (hUCV-MSCs) were isolated and exposed to a sub-lethal concentration (15 µM for 24 h) of H2 O2 in vitro. One week following the injection of bleomycin, 2×105 MSCs or p-MSCs were injected (IT) into the experimental PF. The survival rate and weight of mice were recorded, and 14 days after MSCs injection, all mice were sacrificed. Lung tissue was removed from these mice to examine the myeloperoxidase (MPO) activity, histopathological changes (hematoxylin-eosin and Masson's trichrome) and expression of transforming growth factor beta 1 (TGF-ß1) and alpha-smooth muscle actin (α-SMA) through immunohistochemistry (IHC) staining. Results: Compared to the PF+MSC group, p-MSCs transplantation results in significantly decreased connective tissue (P<0.05) and collagen deposition. Additionally, it is determined that lung tissue in the PF+pMSC group has increased alveolar space (P<0.05) and diminished expression of TGF-ß1 and α-SMA. Conclusion: The results demonstrate that MSCT using p-MSCs decreases inflammatory and fibrotic factors in bleomycin-induced PF, while also able to increase the therapeutic potency of MSCT in IPF.

Immunomodulatory Effects of Blood Transfusion on Tumor Size, Metastasis, and Survival in Experimental Fibrosarcoma.

In spite of efforts, blood transfusion is still accompanied with adverse effects such as transfusion-related immunomodulation (TRIM). The current study aimed to evaluate the effects of allogeneic, syngeneic, fresh and storage blood transfusion on the growth and metastasis of tumors and survival in fibrosarcoma bearing BALB/c mice. Twenty-five BALB/c mice were grouped into five groups of equal size. All groups were injected 1.2 × 106 WEHI-164 cells subcutaneously to induce fibrosarcoma tumor. After expansion of the tumor, in four groups (except for the control group), hemorrhage-induced anemia was developed. Twenty-four hours later, blood deficit was replaced by fresh allogeneic, storage allogeneic, fresh syngeneic and storage syngeneic blood transfusion, respectively. After a blood transfusion, for 13 days, the tumor size and survival of the mice were evaluated. In the day 20, the mice were sacrificed and their spleen tissues were evaluated for TRIM induced metastasis. Tumor size increase in the groups that received allogeneic (fresh and storage) and storage syngeneic blood transfusion was significantly higher than the control group (P value < 0.05). However, no significant difference was present in survival between the experiment groups and the control group. There was no metastasis in none of groups at the end of the study. Allogeneic and storage blood transfusion could have immunomodulatory effects such as increased tumor size. However, it seems that fresh and syngeneic blood transfusion have no effects on tumor growth in fibrosarcoma bearing mice. Further evidence may prove that more attention is warranted in blood transfusion into cancer cases.