Distribution of multi-level B cell subsets in thymoma and thymoma-associated myasthenia gravis.

B-cell subsets in peripheral blood (PB) and tumor microenvironment (TME) were evaluated to determine myasthenia gravis (MG) severity in patients with thymoma-associated MG (TMG) and the distribution of B cells in type B TMG. The distribution of mature B cells, including Bm1-Bm5, CD19+ and CD20+ B cells and non-switched (NSMBCs) and switched (SMBCs) memory B cells, were determined in 79 patients with thymoma or TMG. Quantitative relationships between the T and TMG groups and the TMG-low and TMG-high subgroups were determined. NSMBCs and SMBCs were compared in TME and PB. Type B thymoma was more likely to develop into MG, with types B2 and B3 being especially associated with MG worsening. The percentage of CD19+ B cells in PB gradually increased, whereas the percentage of CD20+ B cells and the CD19/CD20 ratio were not altered. The (Bm2 + Bm2')/(eBm5 + Bm5) index was significantly higher in the TMG-high than in thymoma group. The difference between SMBC/CD19+ and NSMBC/CD19+ B cell ratios was significantly lower in the thymoma than TMG group. NSMBCs assembled around tertiary lymphoid tissue in thymomas of patients with TMG. Few NSMBCs were observed in patients with thymoma alone, with these cells being diffusely distributed. MG severity in patients with TMG can be determined by measuring CD19+ B cells and Bm1-Bm5 in PB. The CD19/CD20 ratio is a marker of disease severity in TMG patients. Differences between NSMBCs and SMBCs in PB and TME of thymomas can synergistically determine MG severity in patients with TMG.

Sodium Butyrate Inhibits the Malignant Proliferation of Colon Cancer Cells via the miR-183/DNAJB4 Axis.

Colorectal carcinoma (CRC) is one of the most common malignant tumors in the digestive tract. It was found that butyric acid could inhibit the expression of miR-183 to slow down malignant progression of CRC in the early stage. However, its regulatory mechanism remains unclear. This study screened the IC50 value of butyrate on inhibition of CRC cells malignant progression. Its inhibitory effects were detected by MTT assay, colony formation experiment, Transwell migration experiment, and apoptosis evaluation by flow cytometry. Next, the expressions of miR-183 and DNAJB4 were, respectively, determined in butyrate treated and miR-183 analog or si-DNAJB4-transfected CRC cells to further detect the role of upregulated miR-183 or silencing DNAJB4 in CRC cells malignant progression. Subsequently, the targeted regulatory relationship between miR-183 and si-DNAJB4 was confirmed by bioinformatic prediction tools and double luciferase report genes analysis method. The regulatory mechanism of butyrate on miR-183/DNAJB4 axis signal pathway was evaluated in molecular level, and verified in nude mouse xerograft tumor model and immunohistochemical analysis tests of Ki67 positive rates. The results displayed that butyrate with increased concentration can hinder the proliferation and improve apoptosis of CRC cells by decreasing the expression of miR-183. Thus, butyrate reduces miR-183 expression and increases DNAJB4 expression via the miR-183/DNAJB4 axis, ultimately inhibiting the malignant progression and increasing apoptosis of CRC. While over expression of miR-183 downregulate the expression of DNAJB4, which can reverse the inhibitory effect of butyrate.

Single-cell sequencing reveals the immune microenvironment landscape related to anti-PD-1 resistance in metastatic colorectal cancer with high microsatellite instability.

BACKGROUND: The objective response rate of microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) patients with first-line anti-programmed cell death protein-1 (PD-1) monotherapy is only 40-45%. Single-cell RNA sequencing (scRNA-seq) enables unbiased analysis of the full variety of cells comprising the tumor microenvironment. Thus, we used scRNA-seq to assess differences among microenvironment components between therapy-resistant and therapy-sensitive groups in MSI-H/mismatch repair-deficient (dMMR) mCRC. Resistance-related cell types and genes identified by this analysis were subsequently verified in clinical samples and mouse models to further reveal the molecular mechanism of anti-PD-1 resistance in MSI-H or dMMR mCRC. METHODS: The response of primary and metastatic lesions to first-line anti-PD-1 monotherapy was evaluated by radiology. Cells from primary lesions of patients with MSI-H/dMMR mCRC were analyzed using scRNA-seq. To identify the marker genes in each cluster, distinct cell clusters were identified and subjected to subcluster analysis. Then, a protein‒protein interaction network was constructed to identify key genes. Immunohistochemistry and immunofluorescence were applied to verify key genes and cell marker molecules in clinical samples. Immunohistochemistry, quantitative real-time PCR, and western blotting were performed to examine the expression of IL-1ß and MMP9. Moreover, quantitative analysis and sorting of myeloid-derived suppressor cells (MDSCs) and CD8+ T cells were performed using flow cytometry. RESULTS: Tumor responses in 23 patients with MSI-H/dMMR mCRC were evaluated by radiology. The objective response rate was 43.48%, and the disease control rate was 69.57%. ScRNA-seq analysis showed that, compared with the treatment-resistant group, the treatment-sensitive group accumulated more CD8+ T cells. Experiments with both clinical samples and mice indicated that infiltration of IL-1ß-driven MDSCs and inactivation of CD8+ T cells contribute to anti-PD-1 resistance in MSI-H/dMMR CRC. CONCLUSIONS: CD8+ T cells and IL-1ß were identified as the cell type and gene, respectively, with the highest correlation with anti-PD-1 resistance. Infiltration of IL-1ß-driven MDSCs was a significant factor in anti-PD-1 resistance in CRC. IL-1ß antagonists are expected to be developed as a new treatment for anti-PD-1 inhibitor resistance.

Follicle-Stimulating Hormone Alleviates Ovarian Aging by Modulating Mitophagy- and Glycophagy-Based Energy Metabolism in Hens.

As a predominant hormone in the reproductive axis, follicle-stimulating hormone (FSH) is known as the primary surviving factor for follicular growth. In this study, the alleviating effect of FSH on aging chicken granulosa cells (GCs) was investigated. Results showed that FSH activated mitophagy and relieved mitochondrial edema in D-gal-induced senescent GCs, which was evidenced by an increased number of mitophagosomes as well as increased mitochondria-light chain 3 (LC3) colocalization. Mitophagy activation was accompanied by the activation of the AMP-activated protein kinase (AMPK) signaling pathway. Furthermore, upregulated glycophagy was demonstrated by an increased interaction of starch-binding domain protein 1 (STBD1) with GABA type A receptor-associated protein-like 1 (GABARAPL1) in D-gal-induced senescent GCs. FSH treatment further promoted glycophagy, accompanied by PI3K/AKT activation. PI3K inhibitor LY294002 and AKT inhibitor GSK690693 attenuated the effect of FSH on glycophagy and glycolysis. The inhibition of FSH-mediated autophagy attenuated the protective effect of FSH on naturally aging GC proliferation and glycolysis. The simultaneous blockage of PI3K/AKT and AMPK signaling also abolished the positive effect of FSH on naturally senescent ovarian energy regulation. These data reveal that FSH prevents chicken ovarian aging by modulating glycophagy- and mitophagy-based energy metabolism through the PI3K/AKT and AMPK pathways.

Valproic Acid Inhibits Glioma and Its Mechanisms.

Glioma is one of the most common intracranial tumors worldwide, and metastasis and chemoresistance remain a challenge in glioma treatment. This study aims to investigate the effect of sodium valproate on the invasion and metastasis of glioma cells and its mechanism. Glioma cell lines were stimulated with VPA at different concentrations and for different durations of action. U87 glioma cells were transfected with Smad4 plasmid and small interfering RNA, and the changes of EMT-related protein indexes in U87 cells after up- or downregulation of Smad4 were detected by Western blotting. Immunohistochemistry was used to detect the differences in the expression of Smad4, TIF1-γ, and TGF-ß proteins in 39 glioma clinical specimens from the Department of Pathology of our hospital. Based on the regulation of EMT-related transcription factors by VPA, our study indicates that VPA inhibits the EMT process of glioma by altering the expression level of Smad4, which is induced by TGF-ß1 to form a Smad3/4 complex, thus inducing the EMT process of the tumor and acting as an antitumor target to inhibit the invasive ability of glioma cells. Sodium valproate inhibits glioma invasion and metastasis through the regulation of Smad4 expression.

Mig-6 could inhibit cell proliferation and induce apoptosis in esophageal squamous cell carcinoma.

BACKGROUND: To investigate the expression and biological functions of mitogen-induced gene 6 (Mig-6) in esophageal squamous cell carcinoma (ESCC). METHODS: The expression of Mig-6 in ESCC tissues and normal esophageal epithelial tissues were measured by immunohistochemistry (IHC) assay. MTT test was applied to detect the proliferative ability of ESCC cells after Mig-6 was upregulated by transfection. A fluid cytology assay was used to detect apoptosis of ESCC cells. Agilent whole human genome oligo microarray was used to screen different expressed genes and the possible signaling pathways which might be involved. RESULTS: The expression of Mig-6 protein was lower in ESCC tissues compared to normal esophageal epithelial tissues. Mig-6 could restrain the ESCC cell growth and induce cell apoptosis. PPAR, CAMs and MAPK signaling pathways might be involved. CONCLUSIONS: Mig-6 might be a new tumor suppressor gene and a possible target for the specific therapy of ESCC.

Two types of immune infiltrating cells and six hub genes can predict the occurrence of myasthenia gravis in patients with thymoma.

Thymoma is the most common primary mass in anterior mediastinum. Although associated with low malignancy, it is often accompanied by myasthenia gravis resulting in poor prognosis. Due to the dual factors of tumor immune tolerance and autoimmune reaction, it is urgent to understand the immune status of MG with thymoma. In this study, RNA sequencing data were obtained from the TCGA and GEO cohorts to identify differentially expressed messenger RNAs and infiltrated immune cells. A total of 121 samples in TCGA and 43 samples in GEO were screened out. The infiltrated immune cells were identified by CIBERSORT, in which Tfh cells and activated DC cells were abnormal in thymoma patients. The differently expressed genes were performed by package LIMMA. The functional characteristics of differently expression genes were analyzed by GO and KEGG; one GO and seven KEGG pathways were both found in both TCGA and GEO cohorts. Meanwhile, 27 common differently expressed genes were obtained and were displayed by a Venn diagram. The TRRUST was used to screen the hub genes for the common 27 different genes and 6 genes were found. Then, PPI networks were constructed. Subsequently, the relationship between SCNAs of common genes and related immune cells tested by TIMER. Kaplan-Meier plots, ROC curve and Cox's expression model for immune infiltration and hub genes were also tested. In conclusion, we found that two types of immune infiltrated cells and six hub genes can predict the occurrence of myasthenia gravis in thymoma patients.

miR-128-3p reduced acute lung injury induced by sepsis via targeting PEL12.

OBJECTIVE: Acute lung injury (ALI) caused by sepsis is clinically a syndrome, which is featured by damage to the alveolar epithelium and endothelium. In this study, we employed mice models of cecal ligation and puncture (CLP) and primary mice pulmonary microvascular endothelial cells (MPVECs) in vitro to investigate the effect of miR-128-3p in ALI caused by sepsis. METHODS: miR-128-3p agomir or randomized control were injected into adult male C57BL/6 mice 1 week before the CLP surgery. We used miR-128-3p agomir or scrambled control to transfect MPVECs and then employed lipopolysaccharide (LPS) stimulation on the cells. Pellino homolog 2 (PELI2) was predicted to be a direct target of miR-128-3p via luciferase reporter assay. MPVECs were cotransfected with lentiviral vector that expressed PELI2 (or empty vector) as well as miR-128-3p-mimics 1 day before LPS stimulation in rescue experiment. Transcriptional activity of caspase-3, cell apoptosis rate, and the expression levels of miR-128-3p, interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and PELI2 were analyzed. RESULTS: Compared with the sham group, the lung of mice in the CLP group showed pulmonary morphological abnormalities, and the expression of IL-6 and IL-1ß, caspase-3 activity, and apoptosis rate were significantly upregulated in the CLP group. Inflammatory factor levels and apoptosis rate were also significantly induced by LPS stimulation on MPVECs. Upregulation of miR-128-3p effectively inhibited sepsis-induced ALI, apoptosis as well as inflammation. miR-128-3p also played a role in antiapoptosis and anti-inflammation in MPVECs with LPS treatment. PEL12 upregulation in MPVECs alleviated miR-128-3p-induced caspase-3 activity inhibition and pro-inflammatory factor production. CONCLUSIONS: miR-128-3p enabled to alleviate sepsis-induced ALI by inhibiting PEL12 expression, indicating a novel treatment strategy of miR-128-3p for sepsis-induced ALI.

Effects of thymectomy on late-onset non-thymomatous myasthenia gravis: systematic review and meta-analysis.

BACKGROUND: The effects of thymectomy on late-onset non-thymomatous myasthenia gravis (NTMG) remain controversial. The objective of this study was to conduct a systematic review in order to answer two questions pertinent to late-onset NTMG: (1) do patients with late-onset NTMG experience the same effects from thymectomy as their early-onset counterparts? (2) Compared with conservative treatment, does thymectomy have any benefits for late-onset NTMG patients? METHODS: We searched the PubMed, EMBASE, and Cochrane Library databases for studies published from January 1, 1950 to March 10, 2021. Outcomes were measured via clinical stable remission/pharmacological remission (CSR/PR) and improvement rates. We used Stata software to analyze the data. RESULTS: We ultimately included a total of 12 observational articles representing the best evidence answering the questions of our study objective. Of these, nine studies, which included 896 patients overall (766 early-onset and 230 late-onset), compared postoperative outcomes between early- and late-onset NTMG. The remaining three articles, which included 216 patients (75 in the thymectomy group and 141 in the conservative-treatment group), compared thymectomy with conservative treatment for late-onset NTMG. The early- versus late-onset NTMG studies demonstrated that patients in the former category were 1.95× likelier than their late-onset counterparts to achieve clinical remission (odds ratio [OR] 1.95; 95% confidence interval [CI] 1.39-2.73; I2 = 0%). No difference was seen in improvement or remission + improvement rates between these two groups. When comparing thymectomy with conservative treatments in late-onset NTMG patients, neither did we observe any difference in CSR/PR. CONCLUSION: We found that late-onset NTMG patients had a lower chance of achieving CSR after thymectomy than early-onset patients. Thymectomy in late-onset NTMG also yielded no benefit to CSR or PR compared with conservative treatments. In late-onset NTMG patients, thymectomy should therefore be performed with caution, and the appropriate cutoff between early- and late-onset MG should be further explored in order to tailor and execute the proper therapeutic strategies.

Quantitative Proteomics Reveals the Dynamic Pathophysiology Across Different Stages in a Rat Model of Severe Traumatic Brain Injury.

BACKGROUND: Severe traumatic brain injury (TBI) has become a global health problem and causes a vast worldwide societal burden. However, distinct mechanisms between acute and subacute stages have not been systemically revealed. The present study aimed to identify differentially expressed proteins in severe TBI from the acute to subacute phase. METHODS: Sixty Sprague Dawley (SD) rats were randomly divided into sham surgery and model groups. The severe TBI models were induced by the controlled cortical impact (CCI) method. We evaluated the neurological deficits through the modified neurological severity score (NSS). Meanwhile, H&E staining and immunofluorescence were performed to assess the injured brain tissues. The protein expressions of the hippocampus on the wounded side of CCI groups and the same side of Sham groups were analyzed by the tandem mass tag-based (TMT) quantitative proteomics on the third and fourteenth days. Then, using the gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and protein-protein interaction (PPI), the shared and stage-specific differentially expressed proteins (DEPs) were screened, analyzed, and visualized. Eventually, target proteins were further verified by Western blotting (WB). RESULTS: In the severe TBI, the neurological deficits always exist from the acute stage to the subacute stage, and brain parenchyma was dramatically impaired in either period. Of the significant DEPs identified, 312 were unique to the acute phase, 76 were specific to the subacute phase, and 63 were shared in both. Of the 375 DEPs between Sham-a and CCI-a, 240 and 135 proteins were up-regulated and down-regulated, respectively. Of 139 DEPs, 84 proteins were upregulated, and 55 were downregulated in the Sham-s and CCI-s. Bioinformatics analysis revealed that the differential pathophysiology across both stages. One of the most critical shared pathways is the complement and coagulation cascades. Notably, three pathways associated with gastric acid secretion, insulin secretion, and thyroid hormone synthesis were only enriched in the acute phase. Amyotrophic lateral sclerosis (ALS) was significantly enriched in the subacute stage. WB experiments confirmed the reliability of the TMT quantitative proteomics results. CONCLUSION: Our findings highlight the same and different pathological processes in the acute and subacute phases of severe TBI at the proteomic level. The results of potential protein biomarkers might facilitate the design of novel strategies to treat TBI.

High expression of KITLG is a new hallmark activating the MAPK pathway in type A and AB thymoma.

BACKGROUND: KIT proto-oncogene ligand (KITLG) is a pleiotropic factor which is found in diverse cancers and is involved in cell proliferation, differentiation, and survival. However, the value of KITLG in thymoma remains unclear. METHODS: A total of 121 thymoma samples from The Cancer Genome Atlas Thymoma (TCGA-THYM) dataset were used to analyze KITLG related genome-wide expression profiles, and microRNA profiles and methylation alterations and a GEO dataset-GSE29695, including 37 samples was used as verification. For cell-based studies, specific small interfering RNA targeting KITLG or a KITLG overexpression vector were used to clarify the changes of the MAPK pathway in an AB thymoma cell line Thy0517. RESULTS: Both datasets showed that high expression of KITLG was significantly associated with type A and AB thymoma. Through multiomic analysis of the TCGA-THYM, it was found that with the high expression of KITLG, there were 220 upregulated and 72 downregulated genes at the mRNA level, 79 positive and 78 negative miRNAs, 28 hypermethylation and 163 hypomethylation regions. In the thymoma cell line Thy0517, it was found that the expression of GRB2 and the phosphorylation levels of BRAF, MEK1/2, and ERK1/2 in the MAPK pathway were positively correlated with the change in KITLG. CONCLUSIONS: High expression of KITLG is a new hallmark of WHO type A and AB thymomas in which it might play a critical role through the activation of the MAPK signaling pathway. Additionally, it is hoped that KITLG will become a potential target for the diagnosis of type A and AB thymoma through further research in the future. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: KIT proto-oncogene ligand (KITLG) is a new hallmark of type A and AB thymomas which induce a series of aberrant alteration of mRNA, miRNA and DNA methylation. The expression of KITLG is significantly higher in type A and AB than other subtypes of thymoma. WHAT THIS STUDY ADDS: KITLG activated the MAPK signaling pathway to promote type A and AB thymoma which might be a potential diagnostic biomarker or target.

Malignant solitary fibrous tumor occurring in the mediastinal pleura showing NAB2ex4-STAT6ex2 fusion and negative STAT6 immunohistochemistry: A case report.

Solitary fibrous tumor (SFT) is a rare clinical tumor, defined as a mesenchymal tumor of fibroblastic origin. A classic SFT is benign in most cases, but its clinical behavior is unpredictable. Lately, molecular analyses has discovered that almost all SFTs harbor an NAB2-STAT6 fusion gene, which is considered specific to this tumor type. Recent studies have suggested that nuclear STAT6 immunoreactivity is a highly sensitive and specific marker of SFTs and can be helpful when diagnosis is inconclusive by conventional methods. We herein report the case of a rare malignant solitary fibrous tumor occurring in the mediastinal pleura. An 82-year-old Chinese man with intermittent breathlessness was referred to our hospital. Chest CT showed a significantly enhanced irregular huge soft tissue mass in the anterior mediastinal area. After radical resection, the immunohistochemistry staining results of the sample showed that STAT6 was negative. The final diagnosis was confirmed by qualitative endpoint reverse transcriptase-polymerase chain reaction technique, showing positive NAB2ex4-STAT6ex2 fusion.

Muscle metabolomics analysis reveals potential biomarkers of exercise­dependent improvement of the diaphragm function in chronic obstructive pulmonary disease.

Decreased diaphragm function is a crucial factor leading to reduced ventilatory efficiency and worsening of quality of life in chronic obstructive pulmonary disease (COPD). Exercise training has been demonstrated to effectively improve the function of the diaphragm. However, the mechanism of this process has not been identified. The emergence of metabolomics has allowed the exploration of new ideas. The present study aimed to analyze the potential biomarkers of exercise­dependent enhancement of diaphragm function in COPD using metabolomics. Sprague Dawley rats were divided into three groups: COPD + exercise group (CEG); COPD model group (CMG); and control group (CG). The first two groups were exposed to cigarette smoke for 16 weeks to establish a COPD model. Then, the rats in the CEG underwent aerobic exercise training for 9 weeks. Following confirmation that exercise effectively improved the diaphragm function, a gas chromatography tandem time­of­flight mass spectrometry analysis system was used to detect the differential metabolites and associated pathways in the diaphragm muscles of the different groups. Following exercise intervention, the pulmonary function and diaphragm contractility of the CEG rats were significantly improved compared with those of the CMG rats. A total of 36 different metabolites were identified in the comparison between the CMG and the CG. Pathway enrichment analysis indicated that these different metabolites were involved in 17 pathways. A total of 29 different metabolites were identified in the comparison between the CMG and the CEG, which are involved in 14 pathways. Candidate biomarkers were selected, and the pathways analysis of these metabolites demonstrated that 2 types of metabolic pathways, the nicotinic acid and nicotinamide metabolism and arginine and proline metabolism pathways, were associated with exercise­induced pulmonary rehabilitation.

Manganese-12 acetate suppresses the migration, invasion, and epithelial-mesenchymal transition by inhibiting Wnt/ß-catenin and PI3K/AKT signaling pathways in breast cancer cells.

BACKGROUND: Breast cancer is the leading cause of cancer-related death in the world, and it is of great value to reveal the molecular mechanisms of breast cancer progression and develop new therapeutic targets. METHODS: Transwell assay is used to analyze the migration and invasion of breast cancer cells. Real-time PCR and western blotting assay are applied to detect the expression levels of epithelial-mesenchymal transition markers and the key members of Wnt/ß-catenin and PI3K/AKT signaling pathways. RESULTS: Manganese-12 acetate (Mn12Ac) significantly inhibited the migration and invasion of MCF7 and MDA-MB-231 breast cancer cells. Western blotting assay further showed that Mn12Ac significantly upregulated E-cadherin, and downregulated N-cadherin and vimentin. We further found that Mn12Ac reduced the mRNA expressions of epithelial-mesenchymal transition-associated transcription factors snail, slug, twist1, and ZEB1 using real-time PCR assay. Importantly, we further found that Mn12Ac significantly reduced the Wnt1 and ß-catenin protein expressions, and suppressed the phosphorylation of PI3K and AKT in MCF7 and MDA-MB-231 breast cancer cells. Very interestingly, we also showed that Mn12Ac decreased the mRNA and protein expressions of programmed cell death ligand 1. CONCLUSION: Taken together, our results suggested that Mn12Ac inhibited the migration, invasion, and epithelial-mesenchymal transition by regulating Wnt/ß-catenin and PI3K/AKT signaling pathways in breast cancer.

Multiplacenta derived stem cell/cytokine treatment increases survival time in a mouse model with radiation-induced bone marrow damage.

Nuclear Warfare and nuclear leakage can result in a large number of patients with radiation-induced bone marrow damage. Based on the fact that hematopoietic stem cells and hematopoietic growth factors are characterized as a novel strategy for therapy, the aim of this study was to explore a safe and routine stem cell/cytokine therapeutic strategy. Allogeneic multiplacenta derived hematopoietic and mesenchymal stem cells/cytokines were intraperitoneally injected into a moderate dose of total body irradiation-induced mouse bone marrow damage model a single time. Then, the mouse posttransplantation survival time, peripheral blood hemoglobin count, bone marrow architecture, and donor cell engraftment were assessed. Each mouse that received placenta-derived stem cells exhibited positive donor hematopoietic and mesenchymal stem cell engraftment both in the bone marrow and peripheral blood after transplantation. The peripheral blood hemoglobin count and survival time were greater in the group with the combined treatment of multiplacenta-derived stem cells and cytokines, compared with model-only controls (both P < 0.001). The blood smear mesenchymal/hematopoietic stem cell count was significantly higher in the combined treatment group than in the mice treated only with placenta-derived cells (28.08 ± 5.824 vs. 20.40 ± 5.989, P < 0.001; 7.74 ± 2.153 vs. 4.23 ± 1.608, P < 0.001, respectively). However, there was no marked change on the bone marrow pathology of any of the experimental mice after the transplantation. These results indicate that for radiation-induced bone marrow damage treatment, multiplacenta-derived stem cells and cytokines can increase the life span of model mice and delay but not abrogate the disease progression. Intraperitoneally transplanted stem cells can survive and engraft into the host body through the blood circulation. Improvement of peripheral blood hemoglobin levels, but not the bone marrow architecture response, probably explains the increase in survival time observed in this study.