Ye Chen

• PhD
• Professor at Zhejiang University

Despite considerable advancements in understanding the mechanisms of ALI, the therapeutic options available in clinical practice remain predominantly supportive, highlighting the urgent need for innovative treatments. In this study, we investigated the potential protective benefits of extracellular vehicles from the probiotic strain Lactiplantibaci...

Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. Ho...

Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. Ho...

Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. Ho...

Osteoarthritis (OA) is a kind of degenerative joint disease usually found in older adults and those who have received meniscal surgery, bringing great suffering to a number of patients worldwide. One of the major pathological features of OA is retrograde changes in the articular cartilage. Mesenchymal stromal cells (MSCs) can differentiate into cho...

Accumulating evidence has confirmed the links between transfer RNA (tRNA) modifications and tumor progression. The present study is the first to explore the role of tRNA methyltransferase 5 (TRMT5), which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma (HCC) progression. Here, based on bioinformatics and clinical...

Ovarian granulosa cell (OGC) is a critical somatic component of the ovary, which provides physical support and the microenvironment required for the developing oocyte. Human OGCs are easy to obtain and culture as a by-product of follicular aspiration performed during in vitro fertilization (IVF) procedures. Therefore, OGCs offer a potent cell sourc...

Acute Myeloid Leukemia In article number 2105811, Yang Yang, Ye Chen, and co‐workers report that acute myeloid leukemia (AML) cells educate regular mesenchymal stromal cells (MSCs) towards an adipogenic differentiation propensity with leukemia promotion capabilities. The fish's gradient colors symbolize the influence of the leukemia cells (in black...

The ADP/ATP carrier (AAC) is crucial for mitochondrial functions by importing ADP and exporting ATP across the inner mitochondrial membrane. However, the mechanism of highly specific ADP recognition and transport by AAC remains largely elusive. In this work, spontaneous ADP binding process to the ground c-state AAC was investigated through rigorous...

Mesenchymal stromal cells (MSCs) are essential elements of the bone marrow (BM) microenvironment, which have been widely implicated in pathways that contribute to leukemia growth and resistance. Recent reports showed genotypic and phenotypic alterations in leukemia patient‐derived MSCs, indicating that MSCs might be educated/reprogrammed. However,...

Specific import of ADP and export of ATP by ADP/ATP carrier (AAC) across the inner mitochondrial membrane are crucial for sustainable energy supply in all eukaryotes. However, mechanism for highly specific substrate recognition in the dynamic transport process remains largely elusive. Here, unguided MD simulations of 22 microseconds in total reveal...

Mammalian mitochondrial tRNA (mt-tRNA) plays a central role in the synthesis of the 13 subunits of the oxidative phosphorylation complex system (OXPHOS). However, many aspects of the context-dependent expression of mt-tRNAs in mammals remains unknown. To investigate the tissue-specific effects of mt-tRNAs, we performed a comprehensive analysis of m...

Mutations in the mitochondrial translation optimization 1 (MTO1) gene can cause hypertrophic cardiomyopathy. Although the functional role of MTO1 deficiency in certain cells is gradually confirmed, the phenotype of MTO1 deficiency in a lymphoblastoid cybrid line is not yet reported. In this study, we characterized changes of mitochondrial function...

Background: Mutations in the mitochondrial translation optimization 1 (MTO1) gene can cause hypertrophic cardiomyopathy. Although the functional role of MTO1 deficiency in certain cells is gradually confirmed, the phenotype of MTO1 deficiency in a lymphoblastoid cybrid line is not yet reported. In this study, we characterized changes of mitochondri...

Accumulating evidence has revealed that mitochondria dynamics and function regulation is essential for the successful mesenchymal stem cell (MSC) differentiation. In the present study, the researchers reported for the first time that Mtu1 defects are correlated with reduced osteogenic differentiation. Using in vitro cultured bone marrow MSCs and st...

The pathophysiology underlying spiral ganglion cell defect-induced deafness remains elusive. Using the whole exome sequencing approach, in combination with functional assays and a mouse disease model, we identified the potentially novel deafness-causative MAP1B gene encoding a highly conserved microtubule-associated protein. Three novel heterozygou...

Nuclear modifier genes have been proposed to modify the phenotypic expression of mitochondrial DNA mutations. Using a targeted exome sequencing approach, here we found that the p.191Gly>Val mutation in mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) interacts with the tRNASer(UCN) 7511A>G mutation in causing deafness. Strikingly, members of a Chine...

The ADP/ATP carrier (AAC) is a transporter responsible for the equal molar exchange of cytosolic ADP and ATP synthesized within mitochondrial matrix across the mitochondrial membrane. Its primary structure consists of three homologous repeats, and each repeat contains a conserved motif that is shared by all members of the mitochondrial carrier fami...

中文概要 目 的 探究 MARVELD2 在中国非综合征耳聋 (NSHL) 人群中的突变频谱和突变频率 创新点 发现 MARVELD2 突变频谱具有明显种族特异性。 中国NSHL人群中的突变位点及频率不同于已报 道的其他人群, 并首次筛选到新致聋候选突变 MARVELD2 c.730G>A。本研究有助于进一步阐 释 MARVELD2 在 NSHL 中的作用。 方法 收集283 例 NSHL 患者外周血, 提取基因组 DNA, 涉及9 对引物覆盖MARVELD2 基因编码区, 经 聚合酶链反应 (PCR) 扩增后 Sanger 测序。测序 结果与参考序列比对, 获得的MARVELD2 变异 位点通过正常人群频率比较、氨基酸保守性分 析、氨基酸性质分析、SIFT 和 PolyPhen 有害...

Auditory function in vertebrates depends on the transduction of sound vibrations into electrical signals by inner ear hair cells. In general, hearing loss resulting from hair cell damage is irreversible because the human ear has been considered to be incapable of regenerating or repairing these sensory elements following severe injury. Therefore, r...

Mtu1(Trmu) is a highly conserved tRNA modifying enzyme responsible for the biosynthesis of τm5s2U at the wobble position of tRNAGln, tRNAGlu and tRNALys. Our previous investigations showed that MTU1 mutation modulated the phenotypic manifestation of deafness-associated mitochondrial 12S rRNA mutation. However, the pathophysiology of MTU1 deficiency...

CXCR4 surface expression is considered an independent prognostic factor for disease relapse and survival in acute myeloid leukemia (AML) patients. Herein, we investigated targetable autophagy-related mechanisms of CXCR4 for AML therapy. Our experiments show that activation of CXCR4 signaling in AML cells increases autophagic activity and decreases...

The chemokine ligand C-X-C motif chemokine ligand 12 (CXCL12) is a kind of small molecules of cytokines that widely expressed in diversified tissues. Recent evidence suggests that CXCL12 plays an important role in the communication of tumor cells with their surrounding microenvironment. The interaction of CXCL12 and its receptors subsequently excit...

Mesenchymal stem cells (MSCs) are progenitors of connective tissues, which have emerged as important tools for tissue engineering due to their differentiation potential along various cell types. In recent years, accumulating evidence has suggested that the regulation of mitochondria dynamics and function is essential for successful differentiation...

Aminoglycosides (AmAn) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world. As previously reported, individuals bearing mitochondrial DNA mutations in the 12S rRNA gene, such as m.1555A>G and m.1494C>T, are...

Nuclear genetic alterations have been widely investigated in papillary thyroid cancer (PTC), however, the characteristics of the mitochondrial genome remain uncertain. We sequenced the entire mitochondrial genome of 66 PTCs, 16 normal thyroid tissues and 376 blood samples of healthy individuals. There were 2508 variations (543 sites) detected in PT...

In this report, we investigated the pathophysiology of novel hypertension-associated mitochondrial tRNAAla 5655A>G mutation. The destabilization of a highly conserved base-pairing (A1-U72) at the aminoacyl acceptor stem by m.5655A>G mutation altered the tRNAAla function. An in vitro processing analysis showed that the m.5655A>G mutation reduced the...

Human mitochondrial DNA (mtDNA) mutations have been associated with a wide spectrum of clinical abnormalities. However, nuclear modifier gene(s) modulate the phenotypic expression of pathogenic mtDNA mutations. In our previous investigation, we identified the human GTPBP3 related to mitochondrial tRNA modification, acting as a modifier to influence...

To better understand how the apoptosis repressor with caspase recruitment domain (ARC) protein confers drug resistance in acute myeloid leukemia (AML), we investigated the role of ARC in regulating leukemia-mesenchymal stromal cell (MSC) interactions. In addition to the previously reported effect on AML apoptosis, we have demonstrated that ARC enha...

FLT3 inhibition has elicited encouraging responses in acute myeloid leukemia (AML) therapy. Unfortunately, unless combined with a bone marrow transplant, disease relapse is frequent. In addition to the acquired point mutations in the FLT3 kinase domain that contribute to FLT3 inhibitor resistance, MEK/ERK signaling is persistently activated in AML...

Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. Nuclear modifier genes are proposed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations. By using an exome sequencing approach, we identified a LHON susceptibility allele (c.572G>T, p.191Gly>Val) in YARS2 gene encoding mitoch...

Tumor cells constantly interact with the surrounding microenvironment. Increasing evidence indicates that targeting the tumor microenvironment could complement traditional treatment and improve therapeutic outcomes for these malignancies. In this paper, we review new insights into the tumor microenvironment, and summarize selected examples of the c...

Mitochondrial genome is responsible for multiple human diseases in a maternal inherited pattern, yet phenotypes of patients in a same pedigree frequently vary largely. Genes involving in epigenetic modification, RNA processing and other biological pathways, rather than “threshold effect” and environmental factors, provide more specific explanation...

Mutations in Gap Junction Beta 2 (GJB2) have been reported to be a major cause of nonsyndromic hearing loss in many populations worldwide. The spectrums and frequencies of GJB2 variants vary substantially among different ethnic groups, and the genotypes among these populations remain poorly understood. In the present study, we carried out a systema...

Mutations in the mitochondrial DNA have been associated with hearing loss. However, the prevalence and spectrum of mitochondrial tRNA mutations in hearing-impaired subjects are poorly understood. In this report, we have investigated the prevalence and spectrum of mitochondrial tRNA(Ser(UCN)) mutations in a large cohort of 2651 Han Chinese subjects...

Aminoglycosides as modifying factors modulated the phenotypic manifestation of mitochondrial rRNA mutations and the incomplete penetrance of hearing loss. In this report, using cybrids harboring the m.1494C>T mutation, we showed that gentamycin aggravated mitochondrial dysfunction in a combination of the m.1494C>T mutation. The m.1494C>T mutation w...

FMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (FLT3-ITD) mutations are common in patients with acute myeloid leukemia (AML). These patients regularly develop resistance to FLT3 inhibitors suggesting that targeted combination drug strategies are needed to enhance AML therapy efficacy. Acquired point mutations of FLT3 ITD gene were sc...

Key Points VCAM-1/VLA-4 triggers reciprocal NF-κB activation in leukemia and stromal cells and mediates cross-talk between leukemia and stromal cells. VCAM-1/VLA-4 and NF-κB signaling plays a pivotal role in the development of leukemia chemoresistance.

CTGF knockdown inhibits REH cell proliferation. (a) Growth curves of REH cells expressing either empty vector (EV) or CTGF shRNA (shCTGF). Statistically significant differences are denoted as follows: **p < 0.01, ***p < 0.001. (b) Cell cycle profiles of REH cells expressing either empty vector (EV) or CTGF shRNA

The bone marrow microenvironment (BME) in acute myeloid leukemia (AML) generates resistance signals that protect AML cells/stem cells from chemotherapy. The mechanisms how the BME might support leukemia cell survival are unclear but elucidation of this process could prove useful for therapy design. Here we report new insights specific to stroma fun...

We have reported that “apoptosis repressor with caspase recruitment domain” (ARC), an antiapoptotic protein promotes leukemia-stromal interactions in part by increasing the expression of CXCR4 in AML cells and of CXCL12 (SDF-1) in mesenchymal stromal cells (MSCs) (Carter et al., ASH 2012). To further understand the mechanisms of action of ARC in me...

Internal tandem duplication (ITD) or point mutation of Fms-like tyrosine kinase 3 (FLT3) and N/KRAS mutations in patients with acute myeloid leukemia (AML) lead to aberrant activation of FLT3 and/or RAS–mitogen-activated protein kinase (MAPK) pathways and are associated with poor prognosis (Kottaridis et al, Leuk Lymphoma Vol. 44:905, 2003; Thiede...

Bone marrow (BM) mesenchymal stromal cells (MSC) protect leukemia cells from chemotherapy-induced apoptosis. CXCR4, the receptor for the stromal-derived factor 1 (SDF-1/CXCL12), is involved in modulating leukemic progenitor cell homing and it is essential for the migration of these cells to the BM niche. As the BM niche imparts favorable survival a...

Recent discoveries demonstrate that leukemia stem cells (LSCs) contribute towards leukemia progression and relapse. Several cell surface and intra-cellular markers including CD34+CD38-, CD123, aldehyde dehydrogenase (ALDH), side-population (SP) dye uptake, and TIM3 have been utilized to detect these cells, but the origin of LSCs has not been clearl...

Connective tissue growth factor (CTGF/CCN2) is involved in extracellular matrix production, tumor cell proliferation, adhesion, migration, and metastasis. Recent studies have shown that CTGF expression is elevated in precursor B-acute lymphoblastic leukemia (ALL) and that increased expression of CTGF is associated with inferior outcome in B-ALL. In...

Acute myeloid leukemia (AML) is a heterogeneous disease that originates in the bone marrow (BM). BM consists of a complex hypoxic micro-environment that includes osteoblasts, osteoclasts, and mesenchymal stromal cells (MSCs).We previously reported that co-culture with BM-derived MSCs induces anti-apoptotic and drug resistant genes in leukemic cells...

Mesenchymal stromal cells (MSCs) are a major component of the leukemia bone marrow (BM) microenvironment. Connective tissue growth factor (CTGF) is highly expressed in MSCs, but its role in the BM stroma is unknown. Therefore, we knocked down (KD) CTGF expression in human BM-derived MSCs by CTGF short hairpin RNA. CTGF KD MSCs exhibited fivefold lo...

We examined the role of microRNAs (miRNAs) in targeting the stromal-derived factor 1α/CXCR4 (SDF-1α/CXCR4) axis to overcome chemoresistance of AML cells. Microarray analysis of OCI-AML3 cells revealed that the miRNA let-7a was downregulated by SDF-1α-mediated CXCR4 activation and increased by CXCR4 inhibition. Overexpression of let-7a in AML cell l...

CXCR4, the receptor for stromal-derived factor-1, is reportedly involved in breast carcinogenesis. However, the mechanisms through which CXCR4 contributes to breast cancer cell growth and metastases are poorly understood. In this study, we examined the putative in vitro and in vivo anti-cancer effects of the specific CXCR4 inhibitor AMD3465. Here,...

1286 CXCR4 surface expression has been reported as an important prognostic marker in AML patients. Our group previously reported that targeting the SDF-1α/CXCR4 axis by CXCR4 inhibition could overcome the resistance of AML cells to chemotherapy both in vitro and in vivo. To further explore the mechanism of targeting CXCR4, we first performed a micr...

1523 We have recently demonstrated that the leukemic bone marrow (BM) niche is highly hypoxic and that hypoxia promotes resistance of leukemic cells to chemotherapy (Benito et al., PLoS One 2011, e23108). Our preliminary data indicate that AML cells surviving chemotherapy in the human xenograft mouse models of leukemia reside within hypoxic areas o...

2626 Hematopoietic cells express a wide range of adhesion molecules and bone marrow (BM) stroma cells produce their corresponding ligands. Through these ligand-receptor pairs, hematopoietic cells interact with their BM microenvironment. The same system is hijacked by AML and often adhesion molecules in leukemia cells and/or their ligands in stroma...

2355 The interaction of bone marrow (BM) mesenchymal stem cells (MSC) and acute myeloid leukemia (AML) cells creates a microenvironment (McrEnv) that supports and regulates the survival and proliferation of leukemic cells. These same BM McrEnv interactions can also create a sanctuary that protects subpopulations of AML blasts from chemotherapy. The...

3518 Within the bone marrow (BM) microenvironment, BM mesenchymal stromal cells (BM-MSC) provide leukemia cells with a rich environment that serves as a sanctuary and protects them from chemotherapeutic agents. Interactions between leukemia cells and BM-MSC are thought to change the behavior of both stroma and leukemia cells resulting in an increas...

3468 Mesenchymal stromal cells (MSC) participate in the generation of the microenvironmental bone marrow niche which protects normal and leukemic stem cells from injuries, including chemotherapy. MSC produce numerous factors that aid in this function; however, little is known about how leukemic cells affect MSC. In this study, paired murine AML cel...

Within the bone marrow (BM) microenvironment, BM mesenchymal stromal cells (BM-MSC) produce cytokines and chemokines and initiate cellular adhesion-mediated signals that tightly regulate normal and malignant hematopoietic cell development. This rich environment serves as a sanctuary for malignant hematopoietic cells, offering protection from chemot...

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The microenvironment contributes and may regulate cancer development, progression and resistance to treatment. Our group reported first the contribution of bone marrow (BM)-derived mesenchymal stromal cells (MSCs) for tumor development and metastasis. Accumulating eviden...

The interactions between hematopoietic cells and the bone marrow (BM) microenvironment play a critical role in normal and malignant hematopoiesis and drug resistance. These interactions within the BM niche are unique and could be important for developing new therapies. Here, we describe the development of extramedullary bone and bone marrow using h...

2391 Connective tissue growth factor (CTGF) regulates extracellular matrix production, chemotaxis, cell proliferation and integrin expression. Recent reports suggest that recombinant CTGF transforms mesenchymal stromal cells (MSCs) into fibroblast like cells and inhibits their differentiation potential. We have recently shown that stable knockdown...

1323 The importance of the tumor microenvironment for cancer development, progression and resistance to treatment has recently been recognized. Our group was first to report the contribution of bone marrow (BM) derived mesenchymal stromal cells (MSCs) for tumor development and metastasis. BM is also the dynamic microenvironment (niche) for normal a...

Fms-like tyrosine kinase-3 (FLT3) inhibitors have been used to overcome the dismal prognosis of acute myeloid leukemia (AML) with FLT3 mutations. Clinical results with FLT3 inhibitor monotherapy have shown that bone marrow responses are commonly less pronounced than peripheral blood responses. We investigated the role of p53 in bone marrow stromal...

2586 Resistance to chemotherapy can be mediated by genetic, epigenetic and microenvironmental causes. Only recently the connection between leukemia growth and survival and the hypoxic state of the BM microenvironment has been appreciated, by work conducted by us and others (Fiegl M et.al. Blood 2009; 113: 1504–1512; Harrison JS et. al., Blood 2002;...

2179 The role of SDF-1α /CXCR4 signaling in leukemia cell/bone marrow microenvironment interactions has recently been established. Activation of CXCR4 induces leukemia cell trafficking and homing into the marrow microenvironment, where the CXCR4 ligand SDF-1α is produced, keeping leukemic cells in close contact with the stromal cells and extracellu...

To develop a protocol for direct hepatic lineage differentiation from early developmental progenitors to a population of mature hepatocytes. Hepatic progenitor cells and then mature hepatocytes from mouse embryonic stem (ES) cells were obtained in a sequential manner, induced by valproic acid (VPA) and cytokines (hepatocyte growth factor, epidermal...

Recent studies suggest that mesenchymal stem cells (MSCs) possess a greater differentiation potential than once thought and that they have the capacity to regenerate damaged tissues/organs. However, the evidence is insufficient, and the mechanism governing the recruitment and homing of MSCs to these injured sites is not well understood. We first ex...

Bone marrow stromal stem cells (BMSSCs) may have potential to differentiate in vitro and in vivo into hepatocytes. Here, we investigated the effects of valproic acid (VPA) involved in epigenetic modification, a direct inhibitor of histone deacetylase, on hepatic differentiation of mouse BMSSCs. Following the treatment of 2.5 mM VPA for 72 hrs, the...

Although different strategies have been established for hepatic differentiation of mesenchymal stromal cells (MSC), further studies are required to define an efficient strategy to produce hepatocytes from stem cells and uncover the mechanisms of hepatic differentiation. Bone marrow mesenchymal stromal cells (BMMSC), isolated from ICR mice, were ind...

Mesenchymal stem cells were initially characterized as plastic adherent, fibroblastoid cells. In recent years, there has been an increasing focus on mesenchymal stem cells since they have great plasticity and are potential for therapeutic applications. Mesenchymal stem cells or mesenchymal stem cell-like cells have been shown to reside within the c...

The differentiation potential of adult stem cells has long been believed to be limited to the tissue or germ layer of their origin. However, recent studies have demonstrated that adult stem cells may encompass a greater potential than once thought. In the present study, we examined whether murine bone marrow derived stromal stem cells (BMSSCs) are...

Embryonic stem (ES) cells, derived from blastocyst-stage of early mammalian embryos, have the potential to differentiate into derivatives of all three embryonic germ layers. Here we reported the first evidence that murine pluripotent ES cells could be induced to differentiate into cardiomyocytes by cyclic adenosine 3',5'-monophosphate (cAMP) in vit...

During the past few years multiple studies have revealed that adult stem cells, including BM origin stem cells, can be transdifferentiated into various cell types, including hepatocyte-like cells, under proper treatments or in a suitable microenvironment. However, little is known about the mechanism of the transdifferentiation, and the treatments e...