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Abstract: Mesenchymal stem cells (MSC) exhibit self-renewal capacity and multilineage differentiation potential, making them attractive for research and clinical application. The properties of MSC can vary depending on specific micro-environmental factors. MSC resides in specific niches with low oxygen concentrations, where oxygen functions as a metabolic substrate and a signaling molecule. Conventional physical incubators or chemically hypoxia mimetic agents are applied in cultures to mimic the original low oxygen tension settings where MSC originated. This review aims to focus on the current knowledge of the effects of various physical hypoxic conditions and widely used hypoxia-mimetic agents-PHD inhibitors on mesenchymal stem cells at a cellular and molecular level, including proliferation stemness, differentiation, viability, apoptosis, senescence, migration, immunomodulation behaviors, as well as epigenetic changes.

Background: Griscelli syndrome type 2 (GS-2) is a rare, autosomal recessive immune deficiency syndrome caused by a mutation in the RAB27A gene, which results in the absence of a protein involved in vesicle trafficking and consequent loss of function of in particular cytotoxic T and NK cells. Induced pluripotent stem cells (iPSC) express genes associated with pluripotency, have the capacity for infinite expansion, and can differentiate into cells from all three germ layers. They can be induced using integrative or non-integrative systems for transfer of the Oct4, Sox2, Klf4, and cMyc (OSKM) transcription factors. To better understand the pathophysiology of GS-2 and to test novel treatment options, there is a need for an in vitro model of GS-2. Methods: here, we generated iPSCs from 3 different GS-2 patients using lentiviral vectors. The iPSCs were characterized using flow cytometry and RT-PCR and tested for the expression of pluripotency markers. In vivo differentiation to cells from all three germlines was tested using a teratoma assay. In vitro differentiation of GS-2 iPSCs into hematopoietic stem and progenitor cells was done using Op9 feeder layers and specified media. Results: all GS-2 iPSC clones displayed a normal karyotype (46XX or 46XY) and were shown to express the same RAB27A gene mutation that was present in the original somatic donor cells. GS-2 iPSCs expressed SSEA1, SSEA4, TRA-1-60, TRA-1-81, and OCT4 proteins, and SOX2, NANOG, and OCT4 expression were confirmed by RT-PCR. Differentiation capacity into cells from all three germ layers was confirmed using the teratoma assay. GS-2 iPSCs showed the capacity to differentiate into cells of the hematopoietic lineage. Conclusions: using the lentiviral transfer of OSKM, we were able to generate different iPSC clones from 3 GS-2 patients. These cells can be used in future studies for the development of novel treatment options and to study the pathophysiology of GS-2 disease., Scientific and Technological Research Council of Turkey (TÜBİTAK)

Fanconi anemia (FA) is a rare genetic disorder characterized by genomic instability, developmental defects, and bone marrow (BM) failure. Hematopoietic stem cells (HSCs) in BM interact with the mesenchymal stem/stromal cells (MSCs); and this partly sustains the tissue homeostasis. MicroRNAs (miRNAs) can play a critical role during these interactions possibly via paracrine mechanisms. This is the first study addressing the miRNA profile of FA BM-MSCs obtained before and after BM transplantation (preBMT and postBMT, respectively). Non-coding RNA expression profiling and quality control analyses were performed in Donors (n = 13), FA preBMT (n = 11), and FA postBMT (n = 6) BM-MSCs using GeneChip miRNA 2.0 Array. Six Donor-FA preBMT pairs were used to identify a differentially expressed miRNA expression signature containing 50 miRNAs, which exhibited a strong correlation with the signature obtained from unpaired samples. Five miRNAs (hsa-miR-146a-5p, hsa-miR-148b-3p, hsa-miR-187-3p, hsa-miR-196b-5p, and hsa-miR-25-3p) significantly downregulated in both the paired and unpaired analyses were used to generate the BM-MSCs' miRNA-BM mononuclear mRNA networks upon integration of a public dataset (GSE16334; studying Donor versus FA samples). Functionally enriched KEGG pathways included cellular senescence, miRNAs, and pathways in cancer. Here, we showed that hsa-miR-146a-5p and hsa-miR-874-3p were rescued upon BMT (n = 3 triplets). The decrease in miR-146a-5p was also validated using RT-qPCR and emerged as a strong candidate as a modulator of BM mRNAs in FA patients.

Fanconi anemia (FA) is a rare genetic disorder characterized by genomic instability, developmental defects, and bone marrow (BM) failure. Hematopoietic stem cells (HSCs) in BM interact with the mesenchymal stem/stromal cells (MSCs); and this partly sustains the tissue homeostasis. MicroRNAs (miRNAs) can play a critical role during these interactions possibly via paracrine mechanisms. This is the first study addressing the miRNA profile of FA BM-MSCs obtained before and after BM transplantation (preBMT and postBMT, respectively). Non-coding RNA expression profiling and quality control analyses were performed in Donors (n = 13), FA preBMT (n = 11), and FA postBMT (n = 6) BM-MSCs using GeneChip miRNA 2.0 Array. Six Donor-FA preBMT pairs were used to identify a differentially expressed miRNA expression signature containing 50 miRNAs, which exhibited a strong correlation with the signature obtained from unpaired samples. Five miRNAs (hsa-miR-146a-5p, hsa-miR-148b-3p, hsa-miR-187-3p, hsa-miR-196b-5p, and hsa-miR-25-3p) significantly downregulated in both the paired and unpaired analyses were used to generate the BM-MSCs' miRNA-BM mononuclear mRNA networks upon integration of a public dataset (GSE16334; studying Donor versus FA samples). Functionally enriched KEGG pathways included cellular senescence, miRNAs, and pathways in cancer. Here, we showed that hsa-miR-146a-5p and hsa-miR-874-3p were rescued upon BMT (n = 3 triplets). The decrease in miR-146a-5p was also validated using RT-qPCR and emerged as a strong candidate as a modulator of BM mRNAs in FA patients.

Imbalance between free radicals and antioxidants causes oxidative stress by the accumulation of reactive oxygen species (ROS) in the tissues and organs. Oxidative stress occurs in many damaged conditions, and the increase of ROS and reduction of antioxidants enhances inflammation, apoptosis, fibrosis and may worsen the pathology leading to organ failure. The potential therapies aim to increase antioxidants and decrease ROS. Mesenchymal stem cells (MSCs) isolated from the stroma of various tissues are multipotent cells and have beneficial effects on several diseases with their immunomodulation and regeneration capacities. MSCs trigger the proliferation of the cells with various secretory factors, reduce oxidative stress and decrease apoptosis, inflammation, fibrosis and thus, increase regeneration. However, survival, engraftment, and differentiation problems of transplanted MSCs restrict their protective and regenerative effects. Preconditioning of MSCs with several factors, such as cytokines, hypoxia, chemical agents, pharmacological drugs, physical factors and growth factors, enhances their repairing efficacy for injury and disease models. This review is mainly focused on insulin-like growth factor (IGF-1) and hepatocyte growth factor (HGF), and discusses the research on MSC priming/induction with IGF-1 and HGF stimulation either by supplementation or overexpression that can enhance the regenerative potential of MSCs on various oxidative stress conditions such as acute/chronic kidney diseases, lung injury, cancer, metabolic and cardiovascular diseases.

Background & Aim Focal Segmental Glomerulosclerosis (FSGS) is one of the leading causes of end-stage kidney disease requiring renal replacement therapy for survival. It is characterized by massive proteinuria that results in hypoalbuminemia, edema and hyperlipidemia. and is known as irreversible kidney disease that steroid-based drugs only slow down the progression. The use of Mesenchymal stem cells (MSCs) has been successful in the treatment of glomerular diseases. The biggest challenge of the MSC application is its engraftment into the site of injury and its loss due to the poor microenvironment. Preconditioning of MSCs by particular growth factors such as insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) increases their migration, immunomodulation and survival. IGF-1 and HGF have been proposed as promising therapeutic agents in recent years and are especially preferred in renal diseases with their renotrophic and nephroprotective effects. Therefore we aimed to test the effect of IGF-1 and HGF-preconditioned MSCs in a rat model of FSGS. Methods, Results & Conclusion Preconditioning of MSCs was performed by 10 ng/ml IGF-1 and 20 ng/ml HGF and designated as iMSCs. Rat (Sprague-Dawley) FSGS model was technically induced by a single-dose intraperitoneal administration of Puromycin Aminonucleoside (PAN) (150 mg/kg). There were PBS, MSC and iMSC treatment groups (n=6/gr77). The occurrence of FSGS was assessed by biochemistry (i.e. elevated urinary protein/creatinine (P/C) ratio), immunohistochemistry (i.e. decreased glomerular SYNPO protein level) and electron microscopy (i.e. presence of podocyte effacement). We applied 2 × 105 MSC or preconditioned MSC intravenously on the day of 4 following PAN administration. The effect of treatment was assessed by urinary P/C ratios in 24-hour urine which was collected on the treatment day of 9. iMSC treatment significantly decreased proteinuria (p As a result of our study, we demonstrated that iMSCs can partially reverse the glomerular damage and reduce proteinuria with regenerating glomerular filtering apparatus in the PAN model of FSGS and therefore may offer a new therapeutic strategy for human FSGS.

HOX and TALE transcription factors are important regulators of development and homeostasis in determining cellular identity. Deregulation of this process may drive cancer progression. The aim of this study was to investigate the expression of these transcription factors in the bone marrow derived mesenchymal stem cells (BM-MSCs) of Fanconi anemia (FA) patients, which is a cancer-predisposing disease. Expression levels of HOX and TALE genes in BM-MSCs were obtained from FA patients and healthy donors by RT-qPCR and highly conserved expression levels were observed between patient and donor cells, except PKNOX2, which is a member of TALE class. PKNOX2 was significantly downregulated in FA cells compared to donors (P

HOX and TALE transcription factors are important regulators of development and homeostasis in determining cellular identity. Deregulation of this process may drive cancer progression. The aim of this study was to investigate the expression of these transcription factors in the bone marrow derived mesenchymal stem cells (BM-MSCs) of Fanconi anemia (FA) patients, which is a cancer-predisposing disease. Expression levels of HOX and TALE genes in BM-MSCs were obtained from FA patients and healthy donors by RT-qPCR and highly conserved expression levels were observed between patient and donor cells, except PKNOX2, which is a member of TALE class. PKNOX2 was significantly downregulated in FA cells compared to donors (P 0.05). PKNOX2 expression levels did not change with diepoxybutane (DEB), a DNA crosslinking agent, in either donor or FA cells except one patient's with a truncation mutation of FANCA. A difference of PKNOX2 protein level was not obtained between FA patient and donor BM-MSCs by western blot analysis. When human TGF-β1 (rTGF-β1) recombinant protein was provided to the cultures, PKNOX2 as well as TGF-β1 expression increased both in FA and donor BM-MSCs in a dose dependent manner. 5 ng/mL rTGF-β stimulation had more dominant effect on the gene expression of donor BM-MSCs compared to FA cells. Decreased PKNOX2 expression in FA BM-MSCs may provide new insights into the molecular pathophysiology of the disease and TGF-β1 levels of the microenvironment may be the cause of PKNOX2 downregulation.

Transforming growth factor beta (TGF-beta) secretion from cells in the bone marrow (BM) niche affects hematopoietic stem cell (HSC) fate and has a cardinal role in HSC quiescence. BM mesenchymal stem cells (BM-MSCs), a component of the BM niche, may produce abnormal levels of TGF-beta in Fanconi anemia (FA) and may play a role in bone marrow failure. Here, we molecularly and cellularly characterized FA BM-MSCs by addressing their immunophenotype, proliferation- and differentiation- capacity, reactive oxygen species (ROS) production, senescence activity as well as expression and secretion levels of TGF-beta isoforms. In ten FA patients, mutations were detected in FANCA (n = 7), FANCG (n = 1) and FANCD2 (n = 2) genes. The immunophenotype, with the exception of CD29, and differentiation capacity of FA BM-MSCs were similar to healthy donors. FA BM-MSCs showed decreased proliferation, increased ROS level and an arrest in G2 following DEB treatment. beta-galactosidase staining indicated elevated senescence of FANCD2-deficient cells. FA BM-MSCs displayed TGF-beta 1 mRNA levels similar to donor BM-MSCs, and was not affected by DEB treatment. However, secretion of TGF-beta was absent in FA-D2 BM-MSCs. Absence of TGF-beta secretion may be related to early onset of senescence of the FANCD2-deficient BM-MSCs. The proliferative response of FA-D2 BM-MSCs to rTGF-beta 1 was not different from FANCA-deficient and donor cells and raises the possibility that rTGF-beta 1 may reverse the senescence of the FANCD2-deficient BM-MSCs which needs to be investigated further.

Background aims TNFR family member glucocorticoid-induced tumor necrosis factor–related receptor (GITR/TNFRSF18) activation by its ligand glucocorticoid-induced TNF-related receptor ligand (GITRL) have important roles in proliferation, death and differentiation of cells. Some types of small cell lung cancers (SCLCs) express GITR . Because mesenchymal stromal cells (MSCs) may target tumor cells, we aimed to investigate the effect of MSCs carrying GITRL overexpressing plasmid on the proliferation and viability of a GITR + SCLC cell line (SCLC-21H) compared with a GITR – SCLC cell line (NCI-H82). Methods Electroporation was used to transfer pGITRL ( GITRL gene carrying plasmid) or pCR3 (mock plasmid) into MSCs. Flow cytometry and semi-quantitative polymerase chain reaction were used to characterize the transfected MSCs. Following SCLC-21H or NCI-H82 cell lines were co-cultured with pGITRL-MSCs. Results Proliferation of NCI-H82 was increased in all types of co-cultures while SCLC-21H cells did not. GITRL expressing MSCs were able to induce cell death of SCLC-21H through the upregulation of SIVA1 apoptosis inducing factor. Conclusions The influence of MSCs on SCLC cells can vary according to the cancer cell subtypes as obtained in SCLC-21H and NCI-H82 and enabling GITR-GITRL interaction can induce cell death of SCLC cell lines.

Human mesenchymal stromal cells (MSCs) from different parts of the body (i.e. bone marrow, BM) have distinct cellular and molecular features including global gene expression profiles. Quantitative polymerase chain reaction is a reliable method used in the quantification of gene expression. Correct assessment of target gene expression mostly depends on the reference gene (RG) of choice. Herein, expression levels of RGs (n = 19) in adipo-/osteogenic-differentiated and control (uninduced) BM-MSCs from donors were measured using the RealTime ready Human Reference Gene Panel. Characterization of BM-MSCs was assessed using in vitro differentiation by histochemical staining and immunophenotyping of cells by flow cytometric analysis. BM-MSCs successfully differentiated into adipogenic and osteogenic lineages. When three groups were analyzed together, the NormFinder and GeNorm software programs identified PBGD as the most stable RG. GeNorm also reported G6PDH as the other stable gene. Due to their low expression, PBGD and G6PDH were not suitable RG candidates. RPLP0 had slightly lower stability but very high expression, rendering it as the best RG. When either adipogenic- or osteogenic-induced MSCs were analyzed with control BM-MSCs, the most stable RGs with high expression levels were revealed to be GAPDH and RPLP0. Even though ACTB had the highest expression, its stability was low.

WOS: 000332000400025 PubMed: 24381109 In this study we have retrospectively analysed the mutation spectrum of the 351 Familial Mediterranean fever patients referred to KA +/- rA +/- kkale University Faculty of Medicine, Department of Medical Genetics Laboratory over a period of 5 years and compared them with Turkey's mean. We have found 11 different mutations, including rare mutations such as F479L, K695R, M680I(G/A) and 45 different genotypes showing the heterogeneity of MEFV mutations in Central Anatolia. The most three prevalent mutations were M694V (14.8 %), E148Q (7.1 %) and M680I(G/C) (4.1 %) in accordance with the literature. We have also investigated R202Q in our routine molecular diagnosis. Mutation causing R202Q (c.605G > A) change was described as a frequent polymorphism and G allele was found in linkage disequilibrium (LD) with M694V. There are limited number of studies investigating R202Q, some of them implicate that its homozygote state is disease causing. We showed the high frequency of R202Q (23.7 %) with and without M694V in all the groups analysed and its high LD rate with M694V in the diagnosed group. Our study is reflecting the mutational heterogeneity of MEFV and summarize mutational spectrum of Turkey's geographical regions and overall Turkey.

Background The exposure of lung to noxious agents or gasses leads to injury, which further enhances repair mechanisms by promoting the proliferation and differentiation of lung stem cells. These cells could help preserve the anatomical structure and the function of the organ. Unfortunately in many lung diseases, 'this scenario' is changed and injury progresses despite repair mechanisms or conventional treatment. Objective This review summarizes the research on lung stem cells by giving an overview of the biology, function, niches and signaling that play role in lung stem cells and further of the regeneration of the lung. It also highlights the most common lung pathologies thought to be a result of a defective remodeling and overviews the clinical trials having results or publications, which are performed on the field. Conclusion Though not yet approved for clinical usage, the application of stem cell therapies shown to be safe and with minimal adverse effects could be an alternative treatment to many lung diseases giving a hope for the future of severely ill patients refractory to the current therapies.

Authors: Though bone marrow transplantation is the current option of Fanconi aplastic anemia treatment, an improved understanding of hematopoietic stem cells (HSCs) exhaustion in Fanconi anemia (FA) may open the way of new therapeutic strategies. Our work has focused on the cross talk between mesenchymal stem cells (MSCs) and HSCs in FA. Coexistence of developmental malformations in FA, first raised the question of a possible interaction of FA proteins with developmental proteins. Expression of genes encoding HOX/TALE transcription factors starts early in development and their defects can cause developmental malformations.

WOS: 000263798400019 PubMed: 18389382 Familial Mediterranean Fever (FMF) is an autosomal recessive genetic disorder characterised by recurrent and self-limited abdominal pain, synovitis and pleuritis. MEFV gene mutations are responsible from the disease and its protein product, pyrin or marenostrin, plays an essential role in the regulation of the inflammatory reactions. MEFV gene contains 10 exons and most of the mutations have been found on the last exon. Up to date, 152 mutations and polymorpisms have been reported inwhere V726A, M694V, M694I, M680I and E148Q are the most common mutations. In this study, MEFV allele frequencies of 136 individuals (60 from Pediatry, 76 from Internal Medicine) have been evaluated, and compared with each other. Asymptomatic individuals with FMF family history (4 from Pediatry, 6 from Internal Medicine) were excluded from the analysis. The prominent mutations indicated in the Pediatry group are V726A, M694V and M680I (G/C) and with the allele frequency of 0.06, 0.05 and 0.04 respectively while they were E148Q, M694V, M680I (G/C) in the Internal Medicine group with the allele frequency of 0.12, 0.08 and 0.04. The E148Q mutation is significantly overrepresented in the adult referrals (P = 0.02). Mutation on both alleles was observed in only 12% of cases. Overall mutation frequency was low, seen in 26.2% (66/252). However, when only diagnosed patients were analyzed it is 72.7% (16/22). It is also interesting that 63% of individuals are female that there may be sex influence on FMF phenotype.

Esendagli, Gunes/0000-0003-4865-2377; WOS: 000262496900006 PubMed: 19164932 The presence of CD40 on carcinoma cells is an important factor for the generation of tumor-specific responses induced by CD40 ligation. In an N-methyl-N-nitrosourea (MNU)-induced autochthonous mammary tumor model, we analyzed the immune features of primary tumor cells. Here, CD40 was frequently detected on the primary tumor cultures and selectively expressed on the malignant mammary tissue in vivo. On the other hand, every mammary tumor cell culture had a heterogeneous and reduced expression of proinflammatory TNF alpha, IL-1 beta, IL-6 and CXCL1 cytokines compared to normal mammary epithelial cells. Low-efficiency transfection of CD40 ligand (CD40L) gene enhanced the expression of proinflammatory cytokines in the tumor cells, and strengthened allogeneic immune reactions and costimulatory activity which may help overwhelming suppressive features of the tumor. Eczacibasi Scientific Research; Hacettepe UniversityHacettepe University [05DO3104001] This study was supported by Eczacibasi Scientific Research and Award Fund, and Hacettepe University Scientific Research Unit ( project no. 05DO3104001). We wish to thank Dr. Cemaliye Akyerli for her helpful supervision in real time RT-PCR analysis.

The aim of this study was to screen infertile men for HFE H63D mutation in correlation with clinical characteristics of infertile men (sperm concentration, sperm motility, morphology, testicular volume, Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH) and total Testosterone levels) and find out if the HFE H63D mutation has an effect on male infertility. After excluding hormonal treatment, any scrotal pathology, having any systemic diseases such as diabetes mellitus, sickle cell anemia and microdeletions of the Y chromosome, a total of 148 infertile men with age range between 17 and 52-years-old (average age 29.6 ± 7.2) were enrolled into the study. Our analysis indicates that the mean FSH levels are significantly higher (6.3 ± 4.6 mIU/ml, P = 0.03), whereas sperm motility is significantly lower (36.6 ± 28.1%, P = 0.01) in the infertile men with the HFE H63D mutation compared with subjects lacking this mutation. Comparison of allele frequencies of the infertile men with Ts < 50% versus the infertile men with Ts > 50% revealed a significant difference as expected (P = 0.001, OR = 0.14, %95 CI = 0.04-0.44). Comparison of allele frequencies of infertile men with abnormal sperm motility versus infertile men with normal sperm motility revealed a highly significant difference (P = 0.005, OR = 3.11, %95 CI = 1.41-6.86). Thus, the HFE H63D mutation seems to be an important risk factor for impaired sperm motility and is clinically associated with male infertility. © 2008 Springer Science+Business Media B.V., KÜ AF 03/08.01.03, Acknowledgments This work was supported by Kirikkale University Research Found (KÜ AF 03/08.01.03). We thank the infertility patients who made this analysis possible.

Esendagli, Gunes/0000-0003-4865-2377; WOS: 000262991000009 PubMed: 18987061 N-methyl-N-nitrosourea (MNU), a highly potent carginogen, is widely used to generate mammary tumours in murine species. In a model of MNU-induced mammary carcinogenesis using immature female Sprague-Dawley rats, large mammary tumours (largest dimension >= 0.5 cm) were obtained within a very short period of time. In addition, in the rats bearing MNU-induced mammary carcinomas, there were a number of tumours whose origins were not from mammary tissue but from several different tissues and from mammary non-epithelial tissue. The tumours were of mesenchymal or epithelial origin and they were located in the inguinal region. These tumours were diagnosed as fibroadenoma, combined tubular adenoma and fibroadenoma, hyperkeratotic papilloma, keratinous cyst and malignant peripheral nerve sheath tumour (MPNST) with smooth muscle differentiation. The occurrence of these other tumours in addition to the development of the mammary carcinomas may be attributed to a direct local effect of the intraperitoneal administration of MNU during the sexual development of the immature rats. In the MNU-induced mammary tumour model, coexistence of tumourigenesis in various non-mammary tissues should be considered an important factor that may interfere with experimental procedures and results and also the quality of life of the tumour-bearing animals. Eczacibasi Scientific Research and Award Fund; Hacettepe University Scientific Research UnitHacettepe University [05DO3104001] This study was supported by grants from the Eczacibasi Scientific Research and Award Fund and the Hacettepe University Scientific Research Unit (project no. 05DO3104001). We Wish to thank Dr Sibel Percinel for her helpful supervision in the histopathological evaluations.

45th Annual Meeting of the American-Society-of-Hematology -- DEC 06-09, 2003 -- SAN DIEGO, CALIFORNIA Esendagli, Gunes/0000-0003-4865-2377; WOS: 000186537101986 … Amer Soc Hematol

Regulatory microRNAs (miRNAs) are involved in the molecular control of hematopoiesis and diseases that result from aberrations during this process. Bone marrow (BM) transplantation is a commonly used therapy for patients with certain hematopoietic diseases. Prior to BM transplantation, donors are occasionally treated with granulocyte colony-stimulating factor (G-CSF) to increase the number of hematopoietic stem or progenitor cells in the collected stem cell product. Here we aimed to assess the effects of G-CSF priming on miRNA expression of BM derived mesenchymal stromal/stem cells (BM-MSCs) from healthy donors. Previously isolated and characterized BM-MSCs from 3 days G-CSF (10 μg/kg/d) treated (n=5) and untreated (n=8) healthy donors were used for miRNA expression profiling with Affymetrix GeneChip 2.0 Array. Following Robust Multi-array Average (RMA) normalization, data analysis was carried out in Partek Genomics Suite software package (Partek Incorporated). Differentially expressed miRNAs between G-CSF primed and unprimed groups were determined (p A total of 2156 miRNAs were upregulated whereas 2436 miRNAs were downregulated after in-vivo G-CSF priming. The expression of hp_hsa-mir-1238 and has-miR-3180-3p non-coding RNAs was significantly increased in G-CSF primed BM-MSCs (p Disclosures No relevant conflicts of interest to declare.