更新于：2024-11-01

PDGFD

更新于：2024-11-01

基本信息

别名

IEGF、Iris-expressed growth factor、MSTP036

+ [12]

简介

Growth factor that plays an essential role in the regulation of embryonic development, cell proliferation, cell migration, survival and chemotaxis. Potent mitogen for cells of mesenchymal origin. Plays an important role in wound healing. Induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis. Can initiate events that lead to a mesangial proliferative glomerulonephritis, including influx of monocytes and macrophages and production of extracellular matrix (By similarity).

关联

项与 PDGFD 相关的药物

CR-002(CuraGen Corp.)

靶点

PDGFD

作用机制

PDGFD拮抗剂

在研机构-

原研机构

CuraGen Corp.

在研适应症-

非在研适应症

糖尿病肾病 [+2]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 PDGFD 相关的临床试验

NCT01347190 / Completed临床1期

A Double Blind, Randomized, Placebo Controlled, Single Dose, Phase I Study of the Safety and Tolerability of Alpha1 Proteinase Inhibitor (Human) Inhalation Solution (CR002) in Subjects With Cystic Fibrosis

Study to assess safety and tolerability of a single dose of study-drug administered to Cystic Fibrosis (CF) patients.

开始日期2011-04-01

申办/合作机构

CSL Behring LLC

100 项与 PDGFD 相关的临床结果

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100 项与 PDGFD 相关的转化医学

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0 项与 PDGFD 相关的专利（医药）

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339

项与 PDGFD 相关的文献（医药）

2024-12-01·Cellular and Molecular Life Sciences

Endothelial PDGF-D contributes to neurovascular protection after ischemic stroke by rescuing pericyte functions

Article

作者: Menet, Romain ; ElAli, Ayman ; Lecordier, Sarah ; Bernard, Maxime

AbstractIschemic stroke induces neovascularization of the injured tissue as an attempt to promote structural repair and neurological recovery. Angiogenesis is regulated by pericytes that potently react to ischemic stroke stressors, ranging from death to dysfunction. Platelet-derived growth factor (PDGF) receptor (PDGFR)β controls pericyte survival, migration, and interaction with brain endothelial cells. PDGF-D a specific ligand of PDGFRβ is expressed in the brain, yet its regulation and role in ischemic stroke pathobiology remains unexplored. Using experimental ischemic stroke mouse model, we found that PDGF-D is transiently induced in brain endothelial cells at the injury site in the subacute phase. To investigate the biological significance of PDGF-D post-ischemic stroke regulation, its subacute expression was either downregulated using siRNA or upregulated using an active recombinant form. Attenuation of PDGF-D subacute induction exacerbates neuronal loss, impairs microvascular density, alters vascular permeability, and increases microvascular stalling. Increasing PDGF-D subacute bioavailability rescues neuronal survival and improves neurological recovery. PDGF-D subacute enhanced bioavailability promotes stable neovascularization of the injured tissue and improves brain perfusion. Notably, PDGF-D enhanced bioavailability improves pericyte association with brain endothelial cells. Cell-based assays using human brain pericyte and brain endothelial cells exposed to ischemia-like conditions were applied to investigate the underlying mechanisms. PDGF-D stimulation attenuates pericyte loss and fibrotic transition, while increasing the secretion of pro-angiogenic and vascular protective factors. Moreover, PDGF-D stimulates pericyte migration required for optimal endothelial coverage and promotes angiogenesis. Our study unravels new insights into PDGF-D contribution to neurovascular protection after ischemic stroke by rescuing the functions of pericytes.

2024-10-01·Histopathology

ALK‐rearranged, CD34‐positive spindle cell neoplasms resembling dermatofibrosarcoma protuberans: a study of seven cases

Article

作者: Ameline, Baptiste ; Billings, Steven D ; Mentzel, Thomas ; Rütten, Arno ; Knapp, Calvin ; Fritchie, Karen J ; Azzato, Elizabeth ; Baumhoer, Daniel ; Folpe, Andrew L ; Agrawal, Shruti ; Sukov, William ; Creytens, David ; Astbury, Caroline

AimsThe majority of dermatofibrosarcoma protuberans (DFSP) harbour PDGFB or PDGFD rearrangements. We encountered ALK expression/rearrangement in a PDGFB/D‐negative CD34‐positive spindle cell neoplasm with features similar to DFSP, prompting evaluation of ALK‐rearrangements in DFSP and plaque‐like CD34‐positive dermal fibroma (P‐LDF).Methods and ResultsWe searched the archives of academic institutions for cases previously coded as DFSP and P‐LDF. NGS‐naïve or PDGFB‐negative DFSP were screened for ALK (clone D5F3) expression by immunohistochemistry. NGS or ALK FISH was performed on ALK‐positive cases. Methylome profiling studies were performed and compared with conventional DFSP. One case of “DFSP” and two “P‐LDF” with ALK expression were identified from the archives, while four cases were detected prospectively. These seven cases (6F:1M; 8 months to 76 years) arose in the dermis of the arm (two), scalp, eyelid, thigh, abdomen, and shoulder and ranged from 0.4 to 4.2 cm. Tumours were composed of spindled cells and displayed a storiform growth pattern. Cytologic atypia was absent, and mitotic figures were scarce (0–2/10 HPFs, high power fields). The lesional cells were diffusely positive for CD34 and ALK and negative for S100 protein. By NGS (n = 5), ALK fusion partners included DCTN1 (2), PLEKHH2, and CLIP2 in DFSP‐like cases and FLNA in P‐LDF‐like lesions. ALK FISH was positive in one (of two) cases previously labelled P‐LDF. Methylome profiling of two (of three) ALK‐rearranged DFSP‐like tumours showed clustering with conventional DFSP in the UMAP dimension reduction plot. To date, no tumour has recurred (n = 2; 26, 27 months).ConclusionWe describe a cohort of novel ALK‐rearranged tumours with morphologic features similar to DFSP.

2024-10-01·Cellular Oncology

Exploring the impact of PDGFD in osteosarcoma metastasis through single-cell sequencing analysis

Article

作者: Niu, Gengming ; Min, Daliu ; Cao, Dongyan ; Zhang, Zhichang ; Shen, Zan ; Zhang, Manxue ; Huang, Yujing ; Bai, Yueqing ; Yang, Yue ; Tang, Lina ; He, Aina

AbstractPurposeThe overall survival rate for metastatic osteosarcoma hovers around 20%. Responses to second-line chemotherapy, targeted therapies, and immunotherapies have demonstrated limited efficacy in metastatic osteosarcoma. Our objective is to validate differentially expressed genes and signaling pathways between non-metastatic and metastatic osteosarcoma, employing single-cell RNA sequencing (scRNA-seq) and additional functional investigations. We aim to enhance comprehension of metastatic mechanisms and potentially unveil a therapeutic target.MethodsscRNA-seq was performed on two primary osteosarcoma lesions (1 non-metastatic and 1 metastatic). Seurat package facilitated dimensionality reduction and cluster identification. Copy number variation (CNV) was predicted using InferCNV. CellChat characterized ligand-receptor-based intercellular communication networks. Differentially expressed genes underwent GO function enrichment analysis and GSEA. Validation was achieved through the GSE152048 dataset, which identified PDGFD-PDGFRB as a common ligand-receptor pair with significant contribution. Immunohistochemistry assessed PDGFD and PDGFRB expression, while multicolor immunofluorescence and flow cytometry provided insight into spatial relationships and the tumor immune microenvironment. Kaplan-Meier survival analysis compared metastasis-free survival and overall survival between high and low levels of PDGFD and PDGFRB. Manipulation of PDGFD expression in primary osteosarcoma cells examined invasion abilities and related markers.ResultsTen clusters encompassing osteoblasts, osteoclasts, osteocytes, fibroblasts, pericytes, endothelial cells, myeloid cells, T cells, B cells, and proliferating cells were identified. Osteoblasts, osteoclasts, and osteocytes exhibited heightened CNV levels. Ligand-receptor-based communication networks exposed significant fibroblast crosstalk with other cell types, and the PDGF signaling pathway was activated in non-metastatic osteosarcoma primary lesion. These results were corroborated by the GSE152048 dataset, confirming the prominence of PDGFD-PDGFRB as a common ligand-receptor pair. Immunohistochemistry demonstrated considerably greater PDGFD expression in non-metastatic osteosarcoma tissues and organoids, correlating with extended metastasis-free and overall survival. PDGFRB expression showed no significant variation between non-metastatic and metastatic osteosarcoma, nor strong correlations with survival times. Multicolor immunofluorescence suggested co-localization of PDGFD with PDGFRB. Flow cytometry unveiled a highly immunosuppressive microenvironment in metastatic osteosarcoma. Manipulating PDGFD expression demonstrated altered invasive abilities and marker expressions in primary osteosarcoma cells from both non-metastatic and metastatic lesions.ConclusionsscRNA-seq illuminated the activation of the PDGF signaling pathway in primary lesion of non-metastatic osteosarcoma. PDGFD displayed an inhibitory effect on osteosarcoma metastasis, likely through the suppression of the EMT signaling pathway.

项与 PDGFD 相关的新闻（医药）

2023-04-18

·生物谷

《自然·癌症》：在肺部沉睡多年的乳腺癌细胞为何会突然苏醒？科学家发现衰老相关的微环境是关键

他们发现，在年轻小鼠体内，DTCs低表达血小板源生长因子C（PDGF-C），有利于肿瘤细胞在原发灶以外部位存活，但不足以形成临床可见的转移灶；而在老年小鼠或纤维化的肺中肿瘤转移是乳腺癌致死的最常见原因，在初次诊断后的10-32年期间，晚期乳腺癌复发率为15.53%，在第32年时累积复发率为16.6%[1]。雌激素受体（ER）阳性的乳腺癌占总病例数的70%左右，这种病理分型的乳腺癌可谓十分狡猾，虽然治疗初期预后较好，但是在治疗数十年后，仍然有较大的转移复发风险[2, 3]。这是因为有少数休眠的播散肿瘤细胞（DTCs）持续存在，它们最初悄无声息地潜伏在原发灶以外的部位，一旦被重新激活，便进入增殖状态，最终形成转移灶。所以，探究微环境如何调控DTCs的生存和激活，对于防治乳腺癌的远期复发具有重要意义。近日，由英国癌症研究院Clare Isacke领衔的研究团队，在著名期刊《自然·癌症》上发表论文，阐述了年龄相关的微环境变化调控ER阳性乳腺癌转移性复发的机制[4]。他们发现，在年轻小鼠体内，DTCs低表达血小板源生长因子C（PDGF-C），有利于肿瘤细胞在原发灶以外部位存活，但不足以形成临床可见的转移灶；而在老年小鼠或纤维化的肺中，环境中高水平的PDGF-C可促进DTCs增殖，并上调肿瘤细胞的Pdgfc水平，从而促进疾病进展。本研究揭示了微环境中PDGF-C调节肿瘤进展的新机制，并且为预防ER阳性乳腺癌的转移性复发，提供了可能的治疗靶点。论文截图研究肿瘤远期复发的调控机制，并不是一件容易的事。要想用动物模型研究肿瘤复发，意味着不仅要在动物体内实现DTCs长期存活、不被免疫系统清除，还要短时间内不能成瘤、没有临床表现，等于是放个定时炸弹，还要求它不能立马爆炸，这实在是种很难达成的微妙平衡。 Isacke团队利用ER阳性乳腺癌的同系小鼠模型，将小鼠来源的肿瘤细胞移植到遗传背景一致、免疫功能健全的小鼠体内，成功实现了肺部定植，却又不形成大转移灶。 Isacke和他的同事注意到，在体外培养条件下，ER阳性的小鼠乳腺癌细胞系增殖不活跃，用ER阴性的乳腺癌细胞或正常肺成纤维细胞上清处理后，才能重新开始增殖；原位移植模型也不像ER阴性的细胞能形成明显的转移灶，在肺部和其他器官仅有单个DTCs，或形成小于10个细胞的细胞团。 ER阳性乳腺癌原位移植模型，肺部未见宏观转移考虑到ER阳性乳腺癌长期潜伏的特点，研究人员推测，既然肿瘤可能在几十年后才有转移性复发，会不会是衰老在其中起作用？他们将年轻和年老小鼠模型进行了比较。在年轻小鼠体内，肺部的DTCs呈单个细胞或小细胞团形式，且只有极少数处于增殖状态；而在老年或纤维化的肺中，DTCs形成转移灶的能力更强。年轻（左）与年老（右）小鼠的肺部转移情况接下来，研究人员对年轻和年老小鼠的肺组织进行了RNA-seq分析，发现成纤维细胞激活以及纤维化相关的基因存在差异表达。于是他们又进一步探究了肺纤维化在ER阳性乳腺癌转移性复发中的作用。果不其然，在肺纤维化的小鼠模型中，ER阳性乳腺癌细胞形成转移灶的能力显著增强。结合先前肺成纤维细胞培养上清可刺激ER阳性乳腺癌增殖的结果，研究人员推测老年小鼠体内某些促纤维化因子加速了转移灶的形成。经分析，Isacke团队发现促纤维化的生长因子——PDGF家族的多个基因在年老和年轻小鼠肺部的表达模式并不一致。具体来说，在老年小鼠中，经典的Pdgfa和Pdgfb低表达，而Pdgfc和Pdgfd表达较高；在肺纤维化的模型中，则只有PDGF-C蛋白表达显著升高。要知道，在不同年龄的人类肺组织中，PDGF-C也呈现出类似的表达模式。年轻（左）与老年（右）小鼠PDGF家族基因表达水平除了在肺部具有年龄相关的表达差异之外，Pdgfc在肿瘤细胞中的表达水平也不是一成不变的。虽然体外培养的ER阳性乳腺癌细胞系Pdgfc表达水平很低，但从体内直接分离出的ER阳性乳腺癌细胞却高表达Pdgfc。并且，在老年小鼠肿瘤模型的肺部转移灶中，Pdgfc表达水平也比年轻小鼠肺部的DTCs更高。无论是从微环境还是从肿瘤自身来看，PDGF-C都可能与ER阳性乳腺癌转移性复发脱不了干系！那么PGDF-C究竟对肿瘤和微环境分别有什么影响呢？原来，肿瘤细胞自身的Pdgfc表达主要促进DTCs在肺部形成更多散在的小细胞团，对原发灶和转移部位的肿瘤体积影响不大。换言之，只能让肿瘤散若满天“星”，却聚不成一团“火”。光想靠肿瘤自身实现复发，也没那么容易。其实，动物体内表达PDGF-C受体的主力是成纤维细胞，它们才是复发过程中PDGF-C的主要目标。研究人员发现，PDGF-C可以促进成纤维细胞增殖与迁移，并且有助于成纤维细胞激活、向病灶处聚集。当肺组织向着纤维化的方向发展，DTCs增殖和肿瘤复发不过就是顺水推舟的事了。到这里，PDGF-C“助纣为虐”的角色基本确定了，但同时它也可能成为有效阻断转移性复发的靶点。Isacke团队发现，PDGF受体抑制剂伊马替尼可抑制肿瘤相关成纤维细胞（CAF）的活性，并且使转移灶的体积与数量均减少。伊马替尼可缩小转移病灶肿瘤复发对于患者及其家庭而言，无疑是一记沉重的打击。本研究不仅提出了ER阳性乳腺癌转移性复发的新机制，也进一步确认了年龄带来的复发风险。未来，靶向PDGF-C的药物若能成功应用于临床，或许将有助于减缓ER阳性乳腺癌的肺部进展，造福更多患者。参考文献： [1] Pedersen RN, Esen BÖ, Mellemkjær L, et al. The Incidence of Breast Cancer Recurrence 10-32 Years After Primary Diagnosis. J Natl Cancer Inst. 2022;114(3):391-399. doi:10.1093/jnci/djab202 [2] Ribelles N, Perez-Villa L, Jerez JM, et al. Pattern of recurrence of early breast cancer is different according to intrinsic subtype and proliferation index. Breast Cancer Res. 2013;15(5):R98. doi:10.1186/bcr3559 [3] Pan H, Gray R, Braybrooke J, et al. 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. N Engl J Med. 2017;377(19):1836-1846. doi:10.1056/NEJMoa1701830 [4] Turrell FK, Orha R, Guppy NJ, et al. Age-associated microenvironmental changes highlight the role of PDGF-C in ER+ breast cancer metastatic relapse. Nat Cancer. 2023;10.1038/s43018-023-00525-y. doi:10.1038/s43018-023-00525-y

临床结果临床研究临床终止

2022-06-16

·生物谷

Theranostics: HDAC抑制剂可能用于恢复糖尿病内皮祖细胞和其他干细胞的功能

心血管疾病(CVD)导致糖尿病患者更高的死亡率和致残率，并造成巨大的健康和经济负担。在过去的几十年里，越来越多的临床前证据表明，骨髓来源的内皮祖细胞参与了新生血管和缺血心肌的保护和修复。心血管疾病(CVD)导致糖尿病患者更高的死亡率和致残率，并造成巨大的健康和经济负担。在过去的几十年里，越来越多的临床前证据表明，骨髓来源的内皮祖细胞参与了新生血管和缺血心肌的保护和修复。这导致了基于EPC的自体心脏临床试验，这些试验虽然安全，但仅显示出适度的功能益处。对于心肌梗死(MI)后的自体EPC和/或其他祖细胞为基础的治疗，其质量和功能潜能取决于其来源，并可能受到糖尿病引起的细胞功能障碍等现有共病的影响。以前的研究表明，高血糖是糖尿病的主要危险因素，会导致EPC功能障碍。临床证据进一步表明，从I型和II型糖尿病患者分离的EPC具有降低的动员和归巢、增殖和血管生成能力，这表明糖尿病/高血糖损害抑制了缺血性心脏损伤的EPC修复和血管生成功能。图片来源: https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/35673580/ 近日，来自坦普尔大学的研究者们在Theranostics杂志上发表了题为“Diabetes impairs cardioprotective function of endothelial progenitor cell-derived extracellular vesicles via H3K9Ac inhibition”的文章，该研究发现揭示，糖尿病通过HDACs介导的H3K9Ac下调导致受体心脏内皮细胞血管生成、增殖和细胞生存基因的转录抑制，至少部分地损害了缺血心脏的EPC-EV修复功能。糖尿病患者的心肌梗死(MI)会导致较高的死亡率和发病率。之前已经证明，骨髓内皮祖细胞(EPC)促进心脏新生血管和减轻缺血性损伤。最近，细胞外小泡(EVS)已成为调节干细胞治疗益处的主要旁分泌效应器。基于细胞的自体治疗的适度临床结果提示糖尿病导致EPC功能障碍，也可能反映其EV衍生品。此外，研究表明，翻译后的组蛋白修饰促进了糖尿病引起的血管功能障碍。因此，研究者验证了糖尿病EPC-EVS可能通过调节内皮细胞(ECs)中的组蛋白修饰而失去损伤后心脏修复功能的假说。研究者从非糖尿病(db/+)和糖尿病(db/db)小鼠分离的EPC的培养液中收集EV，并在体外检测它们对受体内皮细胞和心肌细胞的影响，以及它们在永久性结扎冠状动脉左前降支(LAD)和体内缺血/再灌注(I/R)心肌损伤中的修复作用。与db/+EPC-EVS相比，db/db EPC-EVS促进内皮细胞和心肌细胞的凋亡，抑制内皮细胞的成管能力。在体内，与心肌梗死后db/+EPC-EV治疗相比，db/db EPC-EV治疗可抑制心功能，减少毛细血管密度，并增加纤维化。此外，在I/R MI模型中，db/+EPC-EV介导的急性心肌保护在db/db EPC-EVS中消失，db/db EPC-EVS增加免疫细胞浸润、梗塞面积和血浆心肌肌钙蛋白-I。在机制上，db/db EPC-EVS处理的心脏内皮细胞组蛋白3赖氨酸9乙酰化(H3K9Ac)显著低于db/+EPC-EVS。H3K9Ac染色质免疫沉淀测序(CHIP-Seq)结果进一步表明，db/db EPC-EVS降低了H3K9Ac在心脏内皮细胞血管生成、细胞存活和增殖基因中的水平。研究发现，组蛋白脱乙酰酶(HDAC)抑制剂丙戊酸(VPA)部分恢复了糖尿病EPC-EV损伤的H3K9Ac水平、内皮细胞管状形成和活性，并增强了细胞存活和增殖基因Pdgfd和Sox12的表达。此外，研究者观察到VPA治疗改善了db/db EPC介导的心肌梗死后心脏修复和功能。研究机制图图片来源: https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/35673580/ 综上所述，本研究报告了在两种不同的心脏损伤模型中，糖尿病损害了BM-EPC及其分泌的EV的治疗能力。研究者证明了一种新的调节机制，通过糖尿病EPC-EVS介导的HDAC介导的表观遗传学改变，介导受体细胞的功能抑制。使用小分子抑制HDAC酶，VPA可以挽救H3K9Ac水平，从而部分逆转细胞/EV功能。这项研究提供了重要的启示，EPCs在糖尿病中表现出功能受损的ev，至少部分是通过HDAC介导的表观遗传机制。（生物谷 Bioon.com）参考文献 Grace Huang et al. Diabetes impairs cardioprotective function of endothelial progenitor cell-derived extracellular vesicles via H3K9Ac inhibition. Theranostics. 2022 May 21;12(9):4415-4430. doi: 10.7150/thno.70821.