Karim Shamsasenjan

The Effect of Hypoxia on Mesenchymal Stem Cell Biology.

Although physiological and pathological role of hypoxia have been appreciated in mammalians for decades however the cellular biology of hypoxia more clarified in the past 20 years. Discovery of the transcription factor hypoxia-inducible factor (HIF)-1, in the 1990s opened a new window to investigate the mechanisms behind hypoxia. In different cellular contexts HIF-1 activation show variable results by impacting various aspects of cell biology such as cell cycle, apoptosis, differentiation and etc. Mesenchymal stem cells (MSC) are unique cells which take important role in tissue regeneration. They are characterized by self-renewal capacity, multilineage potential, and immunosuppressive property. Like so many kind of cells, hypoxia induces different responses in MSCs by HIF- 1 activation. The activation of this molecule changes the growth, multiplication, differentiation and gene expression profile of MSCs in their niche by a complex of signals. This article briefly discusses the most important effects of hypoxia in growth kinetics, signalling pathways, cytokine secretion profile and expression of chemokine receptors in different conditions.

Immunomodulatory Nature and Site Specific Affinity of Mesenchymal Stem Cells: a Hope in Cell Therapy

Immunosuppressive ability of mesenchymal stem cells (MSCs), their differentiation properties to various specialized tissue types, ease of in vitro and in vivo expansion and specific migration capacity, make them to be tested in different clinical trials for the treatment of various diseases. The immunomodulatory effects of MSCs are less identified which probably has high clinically significance. The clinical trials based on primary research will cause better understanding the ability of MSCs in immunomodulatory applications and site specific migration in the optimization of therapy. So, this review focus on MSCs functional role in modulating immune responses, their ability in homing to tumor, their potency as delivery vehicle and their medical importance.

Implications of mesenchymal stem cells in regenerative medicine

Abstract Mesenchymal stem cells (MSCs) are a population of multipotent progenitors which reside in bone marrow, fat, and some other tissues and can be isolated from various adult and fetal tissues. Self-renewal potential and multipotency are MSC’s hallmarks. They have the capacity of proliferation and differentiation into a variety of cell lineages like osteoblasts, condrocytes, adipocytes, fibroblasts, cardiomyocytes. MSCs can be identified by expression of some surface molecules like CD73, CD90, CD105, and lack of hematopoietic specific markers including CD34, CD45, and HLA-DR. They are hopeful tools for regenerative medicine for repairing injured tissues. Many studies have focused on two significant features of MSC therapy: (I) systemically administered MSCs home to sites of ischemia or injury, and (II) MSCs can modulate T-cell-mediated immunological responses. MSCs express chemokine receptors and ligands involved in cells migration and homing process. MSCs induce immunomedulatory effects on the innate (dendritic cells, monocyte, natural killer cells, and neutrophils) and the adaptive immune system cells (T helper-1, cytotoxic T lymphocyte, and B lymphocyte) by secreting soluble factors like TGF-β, IL-10, IDO, PGE-2, sHLA-G5, or by cell–cell interaction. In this review, we discuss the main applications of mesenchymal stem in Regenerative Medicine and known mechanisms of homing and Immunomodulation of MSCs.

Mesenchymal Stem Cells: New Aspect in Cell-Based Regenerative Therapy

MSCs are multipotent progenitors which reside in bone marrow. They support hematopoietic stem cells homing, self renewal and differentiation in bone marrow. They can also differentiate into osteoblasts, adipocytes, chondrocytes, myocyates and many other tissues. In vivo, when trauma happens, MSCs operate cell renewal and migrate to the damaged tissues to regenerate that injury. In vitro, MSCs are able to proliferate and differentiate to a variety of cell lineages. This makes them a very hopeful tool for cell-based regenerative therapy for large bone defects, maxillofacial skeletal reconstruction, cardiovascular and spinal cord injury and so many other defects. The most important characteristic that make MSCs an excellent tool for cell replacement is their ability to escape from immune rejection. For therapeutic purposes they usually isolated from human bone marrow or fat and they should proliferate in order to reach an adequate number for implantation. Conventionally DMEM medium supplemented with 10% FBS is used for their expansion, but currently autologous platelet rich products are replaced FBS. Platelet granules contain so many growth factors that can support MSCs proliferation.

Biotechnological and biomedical applications of mesenchymal stem cells as a therapeutic system.

Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent progenitor cells which reside in bone marrow (BM), support homing of hematopoietic stem cells (HSCs) and self-renewal in the BM. These cells have the potential to differentiate into tissues of mesenchymal origin, such as fibroblasts, adipocytes, cardiomyocytes, and stromal cells. MSCs can express surface molecules like CD13, CD29, CD44, CD73, CD90, CD166, CXCL12 and toll-like receptors (TLRs). Different factors, such as TGF-β, IL-10, IDO, PGE-2, sHLA-G5, HO, and Galectin-3, secreted by MSCs, induce interaction in cell to cell immunomodulatory effects on innate and adaptive cells of the immune system. Furthermore, these cells can stimulate and increase the TH2 and regulatory T-cells through inhibitory effects on the immune system. MSCs originate from the BM and other tissues including the brain, adipose tissue, peripheral blood, cornea, thymus, spleen, fallopian tube, placenta, Whartons jelly and umbilical cord blood. Many studies have focused on two significant features of MSC therapy: (I) MSCs can modulate T-cell-mediated immunological responses, and (II) systemically administered MSCs home in to sites of ischemia or injury. In this review, we describe the known mechanisms of immunomodulation and homing of MSCs. As a result, this review emphasizes the functional role of MSCs in modulating immune responses, their capability in homing to injured tissue, and their clinical therapeutic potential.

Time--and Concentration--Dependent Effects of Resveratrol on miR 15a and miR16-1 Expression and Apoptosis in the CCRF-CEM Acute Lymphoblastic Leukemia Cell Line.

BACKGROUND Chemotherapy is one of the common approaches in treatment of cancers, especially leukemia. However, drug resistance phenomena reduce the likelihood of treatment success. Resveratrol is a herbal compound which through complicated processes makes some selected cells sensitive to treatment and induction of apoptosis. In the present study, the effects of resveratrol on the expression of miR 15a and miR16-1 and apoptosis in the CCRF-CEM cell line were investigated. MATERIALS AND METHODS The CCRF-CEM cell line was cultured under standard conditions and changes in miR 15a and miR 16-1 expression were analyzed by real time-PCR technique, with attention to reveratrol dose and time dependence. Also, apoptosis is evaluated by flow cytometry using annexin V and PI. RESULTS CCRF-CEM cells underwent dose-dependent apoptotic cell death in response to resveratrol. MiR 15a and miR 16-1 expression was up-regulated after 24 and 48 hours resveratrol treatment (p<0.05). CONCLUSIONS The results of our study indicate that resveratrol induces apoptosis in a time and dose- dependent manner in CCRF-CEM cells. Also, increased expression level of miR 16-1 and miR 15a by means of resveratrol in CCRF-CEM cells might have a role in apoptosis induction and predisposition. According to our results resveratrol can be regarded as a dietary supplement to improve efficacy of anti-leukemia therapies.

The skewed balance between Tregs and Th17 in chronic lymphocytic leukemia

While Tregs maintain self-tolerance and inhibit antitumor responses, T helper (Th)17 cells may enhance inflammatory and antitumor responses. The balance between these two important T-cell subsets has been skewed in many immunopathologic conditions such as autoimmune and cancer diseases. B-cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the western world and is characterized with monoclonal expansion of B lymphocytes. There is evidence which implies that the progression of CLL is associated with expansion of Treg and downregulation of Th17 cells. In this review, we will discuss about immunobiology of Treg and Th17 cells and their role in immunopathogenesis of CLL as well as their reciprocal changes during disease progression.

Toll-like receptors as a key regulator of mesenchymal stem cell function: An up-to-date review

Understanding the role of toll-like receptors (TLRs) in the immunomodulation potential, differentiation, migration, and survival of mesenchymal stem cells (MSCs) is absolutely vital to fully exploiting their MSC-based therapeutic potential. Furthermore, through recognition of exogenous or endogenous ligands produced upon injury, TLRs have been linked to allograft rejection and maintenance of chronic inflammatory diseases, including Crohns disease, rheumatoid arthritis. Characterizing the effect of TLRs in biological control of MSCs fate and function could improve our knowledge about the MSC-based cell therapy and immunotherapy. In this paper, we outline the impacts of TLR activation and mechanisms on MSCs immunomodulatory functions, differentiation, migration, and survivability. Moreover, we indicate that the expression patterns of TLRs in MSCs from different sources.

The insulin-like growth factor-I receptor (IGF-IR) in breast cancer: biology and treatment strategies

Breast cancer is the most common cancer and the second leading cause of cancer-related deaths among women worldwide. Although patients are often diagnosed in the early and curable stages, the treatment of metastatic breast cancer remains a major clinical challenge. The combination of chemotherapy with new targeting agents, such as bevacizumab, is helpful in improving patient survival; however, novel treatment strategies are required to improve clinical outcomes. The insulin-like growth factor-I receptor (IGF-IR) is a tyrosine kinase cell surface receptor which is involved in the regulation of cell growth and metabolism. Previous studies have shown that activation of the IGF-IR signaling pathway promotes proliferation, survival, and metastasis of breast cancer cells. Additionally, overexpression of IGF-IR is associated with breast cancer cell resistance to anticancer therapies. Recently, IGF-IR has been introduced as a marker of stemness in breast cancer cells and there is also accumulating evidence that IGF-IR contributes to the establishment and maintenance of breast cancer epithelial-mesenchymal transition (EMT). Therefore, pharmacological or molecular targeting of IGF-IR could be a promising strategy, in the treatment of patients with breast cancer, particularly in order to circumvent the therapeutic resistance and targeting breast cancer stem/progenitors. Currently, many strategies have been developed for targeting IGF-IR, some have entered clinical trials and some are in preclinical stages for breast cancer therapy. In this review, we will first discuss on the biology of IGF-IR in an attempt to find the role of this receptor in breast cancer and then discuss about therapeutic strategies to target this receptor.

Aberrant Phenotype in Iranian Patients with Acute Myeloid Leukemia

PURPOSE The aim of this study was to evaluate the incidence of aberrant phenotypes and possible prognostic value in peripheral and bone marrow blood mononuclear cells of Iranian patients with AML. METHODS 56 cases of de novo AML (2010-2012) diagnosed by using an acute panel of monoclonal antibodies by multiparametric flowcytometry. Immunophenotyping was done on fresh bone marrow aspirate and/or peripheral blood samples using the acute panel of MoAbs is stained with Phycoerythrin (PE) /fluorescein isothiocyanate (FITC), Allophycocyanin (APC) and Peridinin-chlorophyll protein complex (perCP). We investigated Co-expression of lymphoid-associated markers CD2, CD3, CD7, CD 10, CD19, CD20 and CD22 in myeloblasts. RESULTS Out of the 56 cases, 32 (57.1%) showed AP. CD7 was positive in 72.7% of cases in M1 and 28.5% in M2 but M3 and M4 cases lacked this marker. We detected CD2 in 58.35 of M1cases, 21.40% of M2 cases, 33.3 of M3 and 20% of M5; but M4 patients lacked this marker. The CBC analysis demonstrated a wide range of haemoglobin concentration, Platelet and WBC count which varied from normal to anaemia, thrombocytopenia to thrombocytosis and leukopenia to hyper leukocytosis. CONCLUSIONS Our findings showed that CD7 and CD2 were the most common aberrant marker in Iranian patients with AML. However, we are not find any significant correlation between aberrant phenotype changing and MRD in our population. Taken together, this findings help to provide new insights in to the investigation of other aberrant phenotypes that may play roles in diagnosis and therapeutic of AML.