Production of bioactive recombinant human myeloid‐derived growth factor in <i>Escherichia coli</i> and its mechanism on vascular endothelial cell proliferation

et al. 2021

Front. Oncol.

Kidney renal clear cell carcinoma (KIRC) is the most common primary renal neoplasms. Currently, there are few molecular indicators and therapeutic targets that can be used in diagnostic and prognostic assessment. In this study, we identified the C19orf10 expression in KIRC specimens and explored the diagnostic and prognostic value of C19orf10 in KIRC using TCGA and CPTAC database. Loss-of- and gain-of- function of C19orf10 was performed to investigate the roles of C19orf10 on KIRC cell viability, proliferation, migration and invasion via CCK-8, Edu incorporation and Transwell assays respectively. C19orf10 was overexpressed in KIRC tissues and the elevated C19orf10 expression was closely associated with clinicopathological characteristics of KIRC including histological grade, TNM stage, metastatic status. Silencing C19orf10 significantly suppressed the viability, proliferation, migration and invasion ability, while overexpression of C19orf10 promoted the progression and malignant phenotype in KIRC cells. Furthermore, C19orf10 exerted its carcinogenic function by regulating ZO-1 and PTEN/Akt signaling pathway. Moreover, the Kaplan–Meier survival analysis, Cox regression analysis and receiver operating curve analysis showed that patients with C19orf10 overexpression have poor survival time. C19orf10 could discriminate KIRC patients with high-risk from low-risk. Taken together, C19orf10 contributes to KIRC development via ZO-1 and PTEN/Akt signaling pathway and C19orf10 could serve as a potential diagnostic and prognostic candidate and therapeutic target of KIRC.

Section: Discussionmentioning

confidence: 99%

The Clinical Relevance and Tumor Promoting Function of C19orf10 in Kidney Renal Clear Cell Carcinoma

Liao

et al. 2021

Front. Oncol.

“…Mydgf has been reported to play a crucial role during cardiac repair, such as promoting angiogenesis and inhibiting CM apoptosis 18 , 19 , 27 . Our results display that the proliferation of ECs and FBs was not significantly induced by Mydgf after neonatal cardiac injury, suggesting that Mydgf-induced CM proliferation is the major factor for neonatal heart regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…Our results display that the proliferation of ECs and FBs was not significantly induced by Mydgf after neonatal cardiac injury, suggesting that Mydgf-induced CM proliferation is the major factor for neonatal heart regeneration. It has been reported that Mydgf promotes EC proliferation through phosphorylation of STAT3 on S727 and stimulates STAT3 transcriptional activity 18 , 19 . Our results show that STAT3 is not be activated in Mydgf-treated CMs, indicating that STAT3 signaling is not involved in Mydgf-indcued CM proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…Myeloid-derived growth factor (Mydgf), a paracrine protein produced by bone marrow-derived mononuclear macrophages (MΦs), could reduce scar size and improve heart function after MI 18 . Recently, it has been demonstrated that Mydgf-based biologically active recombinant human Mydgf could mediate endothelial cell (EC) proliferation via the MAPK-STAT3 signaling pathways 19 . However, whether Mydgf could promote CM proliferation and heart regeneration remains unknown, which is the promising approach to reverse cardiac remodeling and hear failure.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mydgf promotes Cardiomyocyte proliferation and Neonatal Heart regeneration

Feng

et al. 2020

Theranostics

Myeloid-derived growth factor (Mydgf), a paracrine protein secreted by bone marrow-derived monocytes and macrophages, was found to protect against cardiac injury following myocardial infarction (MI) in adult mice. We speculated that Mydgf might improve heart function via myocardial regeneration, which is essential for discovering the target to reverse heart failure. Methods: Two genetic mouse lines were used: global Mydgf knockout ( Mydgf-KO ) and Mydgf-EGFP mice. Two models of cardiac injury, apical resection was performed in neonatal and MI was performed in adult mice. Quantitative reverse transcription-polymerase chain reaction, western blot and flow cytometry were performed to study the protein expression. Immunofluorescence was performed to detect the proliferation of cardiomyocytes. Heart regeneration and cardiac function were evaluated by Masson's staining and echocardiography, respectively. RNA sequencing was employed to identify the key involved in Mydgf-induced cardiomyocyte proliferation. Mydgf recombinant protein injection was performed as a therapy for cardiac repair post MI in adult mice. Results: Mydgf expression could be significantly induced in neonatal mouse hearts after cardiac injury. Unexpectedly, we found that Mydgf was predominantly expressed by endothelial cells rather than macrophages in injured neonatal hearts. Mydgf deficiency impeded neonatal heart regeneration and injury-induced cardiomyocyte proliferation. Mydgf recombinant protein promoted primary mouse cardiomyocyte proliferation. Employing RNA sequencing and functional verification, we demonstrated that c-Myc/FoxM1 pathway mediated Mydgf-induced cardiomyocyte expansion. Mydgf recombinant protein improved cardiac function in adult mice after MI injury with inducing cardiomyocyte proliferation. Conclusion: Mydgf promotes cardiomyocyte proliferation by activating c-Myc/FoxM1 pathway and improves heart regeneration both in neonatal and adult mice after cardiac injury, providing a potential target to reverse cardiac remodeling and heart failure.

“…MYDGF was proven to be a promising biotherapeutic prototypic drug for acute myocardial infarction (MI), because it promotes cell survival and stimulates angiogenesis after ischemia reperfusion (Korf-Klingebiel et al, 2015). The accumulating evidence confirms MYDGF's efficacy for cell protection and tissue repair (Wang, Li, Feng, et al, 2020;Yuan et al, 2019;Zhao et al, 2019). The function of MYDGF was explored in subsequent studies with beneficial indications for diseases such as type 2 diabetes or diabetic kidney disease (He et al, 2020;Wang, Li, Guo, et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Mucin‐fused myeloid‐derived growth factor (MYDGF164) exhibits a prolonged serum half‐life and alleviates fibrosis in chronic kidney disease

et al. 2022

British J Pharmacology

Background and Purpose: Although no effective therapy is available to stop or reverse CKD progression targeting its key feature, the loss of peritubular capillaries (PTCs) leading to interstitial fibrosis, myeloid-derived growth factor (MYDGF) with tissue-repairing activities enlightens its therapeutic potential for CKD. However, the extremely short circulatory lifetime (15 min) restricts its application.Experimental Approach: We selected a tandem repeated (TR) region of human CD164 as a carrier to fuse with MYDGF and then investigated for biophysical and pharmacokinetic changes. The MYDGF164 bioactivities were validated in HUVECs and then assessed in HK-2 cells. We also investigated its efficacy in unilateral ureteral obstruction (UUO)-treated mice and in adenine-induced CKD rats.Key results: MYDGF164 was modified with sialoglycans, improving its resistance to serum proteases and increasing its hydrodynamic radius. The half-life of MYDGF164 was significantly prolonged but retained its original cell proliferation, anti-apoptosis, and tubulogenesis activities. It selectively stimulated the proliferation in endothelial and epithelial cells through phosphorylating MAPK1/3. MYDGF164 alleviated capillary rarefaction, hypoxia, renal fibrosis, and tubular atrophy in UUO mice and in adenine-induced CKD rats. MYDGF164 restored renal function, with normalized creatinine and urea levels in adenine-induced CKD rats. Histopathology and immunohistochemistry revealed that MYDGF164 protection was related to its cell-proliferative, anti-apoptosis, and angiogenesis activities. Conclusions and Implications:This study is the first successful example of using a tandem repeated region of hCD164 as a cargo protein for the pharmacokinetic improvement of therapeutic proteins. Our findings highlight the potential of MYDGF164 in alleviating renal fibrosis in CKD.