Biomolecules

2023

Jump to: 2022, 2021, 2020

16 pages, 941 KiB

Open AccessReview

The Role of Gli1⁺ Mesenchymal Stem Cells in Osteogenesis of Craniofacial Bone

by Laidi Wu, Zhixin Liu, Li Xiao, Mi Ai, Yingguang Cao, Jing Mao and Ke Song

Biomolecules 2023, 13(9), 1351; https://doi.org/10.3390/biom13091351 - 5 Sep 2023

Cited by 5 | Viewed by 1931

Abstract

Glioma-associated oncogene homolog 1 (Gli1) is a transcriptional activator of hedgehog (Hh) signaling that regulates target gene expression and several cellular biological processes. Cell lineage tracing techniques have highlighted Gli1 as an ideal marker for mesenchymal stem cells (MSCs) in vivo. Gli1⁺ [...] Read more.

Glioma-associated oncogene homolog 1 (Gli1) is a transcriptional activator of hedgehog (Hh) signaling that regulates target gene expression and several cellular biological processes. Cell lineage tracing techniques have highlighted Gli1 as an ideal marker for mesenchymal stem cells (MSCs) in vivo. Gli1⁺ MSCs are critical for the osteogenesis of the craniofacial bone; however, the regulatory mechanism by which Gli1⁺ MSCs mediate the bone development and tissue regeneration of craniofacial bone has not been systematically outlined. This review comprehensively elucidates the specific roles of Gli1⁺ MSCs in craniofacial bone osteogenesis. In addition to governing craniofacial bone development, Gli1⁺ MSCs are associated with the tissue repair of craniofacial bone under pathological conditions. Gli1⁺ MSCs promote intramembranous and endochondral ossification of the craniofacial bones, and assist the osteogenesis of the craniofacial bone by improving angiopoiesis. This review summarizes the novel role of Gli1⁺ MSCs in bone development and tissue repair in craniofacial bones, which offers new insights into bone regeneration therapy. Full article

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22 pages, 4865 KiB

Open AccessReview

Advances Focusing on the Application of Decellularized Extracellular Matrix in Periodontal Regeneration

by Chao Liang, Li Liao and Weidong Tian

Biomolecules 2023, 13(4), 673; https://doi.org/10.3390/biom13040673 - 14 Apr 2023

Cited by 8 | Viewed by 3307

Abstract

The decellularized extracellular matrix (dECM) is capable of promoting stem cell proliferation, migration, adhesion, and differentiation. It is a promising biomaterial for application and clinical translation in the field of periodontal tissue engineering as it most effectively preserves the complex array of ECM [...] Read more.

The decellularized extracellular matrix (dECM) is capable of promoting stem cell proliferation, migration, adhesion, and differentiation. It is a promising biomaterial for application and clinical translation in the field of periodontal tissue engineering as it most effectively preserves the complex array of ECM components as they are in native tissue, providing ideal cues for regeneration and repair of damaged periodontal tissue. dECMs of different origins have different advantages and characteristics in promoting the regeneration of periodontal tissue. dECM can be used directly or dissolved in liquid for better flowability. Multiple ways were developed to improve the mechanical strength of dECM, such as functionalized scaffolds with cells that harvest scaffold-supported dECM through decellularization or crosslinked soluble dECM that can form injectable hydrogels for periodontal tissue repair. dECM has found recent success in many periodontal regeneration and repair therapies. This review focuses on the repairing effect of dECM in periodontal tissue engineering, with variations in cell/tissue sources, and specifically discusses the future trend of periodontal regeneration and the future role of soluble dECM in entire periodontal tissue regeneration. Full article

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2022

Jump to: 2023, 2021, 2020

27 pages, 5717 KiB

Open AccessSystematic Review

Are Cell-Based Therapies Safe and Effective in the Treatment of Neurodegenerative Diseases? A Systematic Review with Meta-Analysis

by Jasper Van den Bos, Yousra El Ouaamari, Kristien Wouters, Nathalie Cools and Inez Wens

Biomolecules 2022, 12(2), 340; https://doi.org/10.3390/biom12020340 - 21 Feb 2022

Cited by 18 | Viewed by 4630

Abstract

Over the past two decades, significant advances have been made in the field of regenerative medicine. However, despite being of the utmost clinical urgency, there remains a paucity of therapeutic strategies for conditions with substantial neurodegeneration such as (progressive) multiple sclerosis (MS), spinal [...] Read more.

Over the past two decades, significant advances have been made in the field of regenerative medicine. However, despite being of the utmost clinical urgency, there remains a paucity of therapeutic strategies for conditions with substantial neurodegeneration such as (progressive) multiple sclerosis (MS), spinal cord injury (SCI), Parkinson’s disease (PD) and Alzheimer’s disease (AD). Different cell types, such as mesenchymal stromal cells (MSC), neuronal stem cells (NSC), olfactory ensheathing cells (OEC), neurons and a variety of others, already demonstrated safety and regenerative or neuroprotective properties in the central nervous system during the preclinical phase. As a result of these promising findings, in recent years, these necessary types of cell therapies have been intensively tested in clinical trials to establish whether these results could be confirmed in patients. However, extensive research is still needed regarding elucidating the exact mechanism of action, possible immune rejection, functionality and survival of the administered cells, dose, frequency and administration route. To summarize the current state of knowledge, we conducted a systematic review with meta-analysis. A total of 27,043 records were reviewed by two independent assessors and 71 records were included in the final quantitative analysis. These results show that the overall frequency of serious adverse events was low: 0.03 (95% CI: 0.01–0.08). In addition, several trials in MS and SCI reported efficacy data, demonstrating some promising results on clinical outcomes. All randomized controlled studies were at a low risk of bias due to appropriate blinding of the treatment, including assessors and patients. In conclusion, cell-based therapies in neurodegenerative disease are safe and feasible while showing promising clinical improvements. Nevertheless, given their high heterogeneity, the results require a cautious approach. We advocate for the harmonization of study protocols of trials investigating cell-based therapies in neurodegenerative diseases, adverse event reporting and investigation of clinical outcomes. Full article

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14 pages, 1646 KiB

Open AccessFeature PaperArticle

Biologically Relevant In Vitro 3D-Model to Study Bone Regeneration Potential of Human Adipose Stem Cells

by Victor J. B. van Santen, Angela P. Bastidas Coral, Jolanda M. A. Hogervorst, Jenneke Klein-Nulend and Astrid D. Bakker

Biomolecules 2022, 12(2), 169; https://doi.org/10.3390/biom12020169 - 21 Jan 2022

Cited by 2 | Viewed by 2259

Abstract

Standard cell cultures may not predict the proliferation and differentiation potential of human mesenchymal stromal cells (MSCs) after seeding on a scaffold and implanting this construct in a bone defect. We aimed to develop a more biologically relevant in vitro 3D-model for preclinical [...] Read more.

Standard cell cultures may not predict the proliferation and differentiation potential of human mesenchymal stromal cells (MSCs) after seeding on a scaffold and implanting this construct in a bone defect. We aimed to develop a more biologically relevant in vitro 3D-model for preclinical studies on the bone regeneration potential of MSCs. Human adipose tissue-derived mesenchymal stromal cells (hASCs; five donors) were seeded on biphasic calcium phosphate (BCP) granules and cultured under hypoxia (1% O₂) for 14 days with pro-inflammatory TNFα, IL4, IL6, and IL17F (10 mg/mL each) added during the first three days, simulating the early stages of repair (bone construct model). Alternatively, hASCs were cultured on plastic, under 20% O₂ and without cytokines for 14 days (standard cell culture). After two days, the bone construct model decreased total DNA (3.9-fold), COL1 (9.8-fold), and RUNX2 expression (19.6-fold) and metabolic activity (4.6-fold), but increased VEGF165 expression (38.6-fold) in hASCs compared to standard cultures. After seven days, the bone construct model decreased RUNX2 expression (64-fold) and metabolic activity (2.3-fold), but increased VEGF165 (54.5-fold) and KI67 expression (5.7-fold) in hASCs compared to standard cultures. The effect of the bone construct model on hASC proliferation and metabolic activity could be largely mimicked by culturing on BCP alone (20% O₂, no cytokines). The effect of the bone construct model on VEGF165 expression could be mimicked by culturing hASCs under hypoxia alone (plastic, no cytokines). In conclusion, we developed a new, biologically relevant in vitro 3D-model to study the bone regeneration potential of MSCs. Our model is likely more suitable for the screening of novel factors to enhance bone regeneration than standard cell cultures. Full article

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2021

Jump to: 2023, 2022, 2020

12 pages, 2950 KiB

Open AccessArticle

A Standardised Approach to the Biomechanical Evaluation of Tracheal Grafts

by Néstor J. Martínez-Hernández, Jorge Mas-Estellés, Lara Milián-Medina, Cristina Martínez-Ramos, José Cerón-Navarro, José Galbis-Caravajal, Amparo Roig-Bataller and Manuel Mata-Roig

Biomolecules 2021, 11(10), 1461; https://doi.org/10.3390/biom11101461 - 5 Oct 2021

Cited by 8 | Viewed by 2031

Abstract

The ideal tracheal substitute must have biomechanical properties comparable to the native trachea, but currently there is no standardised approach to evaluating these properties. Here we propose a novel method for evaluating and comparing the properties of tracheal substitutes, thus systematising both measurement [...] Read more.

The ideal tracheal substitute must have biomechanical properties comparable to the native trachea, but currently there is no standardised approach to evaluating these properties. Here we propose a novel method for evaluating and comparing the properties of tracheal substitutes, thus systematising both measurement and data curation. This system was tested by comparing native rabbit tracheas to frozen and decellularised specimens and determining the histological characteristics of those specimens. We performed radial compression tests on the anteroposterior tracheal axis and longitudinal axial tensile tests with the specimens anastomosed to the jaw connected to a measuring system. All calculations and results were adjusted according to tracheal size, always using variables relative to the tracheal dimensions, thus permitting comparison of different sized organs. The biomechanical properties of the decellularised specimens were only slightly reduced compared to controls and significant in regard to the maximum stress withstood in the longitudinal axis (−0.246 MPa CI [−0.248, −0.145] MPa) and the energy stored per volume unit (−0.124 mJ·mm⁻³ CI [−0.195, −0.055] mJ·mm⁻³). The proposed method is suitable for the systematic characterisation of the biomechanical properties of different tracheal substitutes, regardless of the size or nature of the substitute, thus allowing for direct comparisons. Full article

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10 pages, 2810 KiB

Open AccessArticle

VEGF Maintains Maternal Vascular Space Homeostasis in the Mouse Placenta through Modulation of Trophoblast Giant Cell Functions

by Xiujun Fan, Shanmugam Muruganandan, Philemon D Shallie, Sabita Dhal, Matthew Petitt and Nihar R Nayak

Biomolecules 2021, 11(7), 1062; https://doi.org/10.3390/biom11071062 - 20 Jul 2021

Cited by 12 | Viewed by 4592

Abstract

Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that acts primarily on endothelial cells, but numerous studies suggest that VEGF also acts on non-endothelial cells, including trophoblast cells. Inhibition of VEGF signaling by excess production of the endogenous soluble VEGF receptor [...] Read more.

Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that acts primarily on endothelial cells, but numerous studies suggest that VEGF also acts on non-endothelial cells, including trophoblast cells. Inhibition of VEGF signaling by excess production of the endogenous soluble VEGF receptor sFlt1 in trophoblast cells has been implicated in several pregnancy complications. Our previous studies and other reports have shown that VEGF directly regulates placental vascular development and functions and that excess VEGF production adversely affects placental vascular development. Trophoblast giant cells (TGCs) line the maternal side of the placental vasculature in mice and function like endothelial cells. In this study, we specifically examined the effect of excess VEGF signaling on TGC development associated with defective placental vascular development using two mouse models an endometrial VEGF overexpression model and a placenta-specific sFlt1 knockdown model. Placentas of endometrial VEGF-overexpressing dams at embryonic days (E) 11.5 and 14.5 showed dramatic enlargement of the venous maternal spaces in junctional zones. The size and number of the parietal TGCs that line these venous spaces in the placenta were also significantly increased. Although junctional zone venous blood spaces from control and VEGF-overexpressing dams were not markedly different in size at E17.5, the number and size of P-TGCs were both significantly increased in the placentas from VEGF-overexpressing dams. In sFlt1 knockdown placentas, however, there was a significant increase in the size of the sinusoidal TGC-lined, alkaline phosphatase-positive maternal blood spaces in the labyrinth. These results suggest that VEGF signaling plays an important role in maintaining the homeostasis of the maternal vascular space in the mouse placenta through modulation of TGC development and differentiation, similar to the effect of VEGF on endothelial cells in other vascular beds. Full article

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10 pages, 721 KiB

Open AccessReview

Engineering the Vasculature of Stem-Cell-Derived Liver Organoids

by Xv Zhang, Liling Tang and Qian Yi

Biomolecules 2021, 11(7), 966; https://doi.org/10.3390/biom11070966 - 30 Jun 2021

Cited by 9 | Viewed by 4366

Abstract

The vasculature of stem-cell-derived liver organoids can be engineered using methods that recapitulate embryonic liver development. Hepatic organoids with a vascular network offer great application prospects for drug screening, disease modeling, and therapeutics. However, the application of stem cell-derived organoids is hindered by [...] Read more.

The vasculature of stem-cell-derived liver organoids can be engineered using methods that recapitulate embryonic liver development. Hepatic organoids with a vascular network offer great application prospects for drug screening, disease modeling, and therapeutics. However, the application of stem cell-derived organoids is hindered by insufficient vascularization and maturation. Here, we review different theories about the origin of hepatic cells and the morphogenesis of hepatic vessels to provide potential approaches for organoid generation. We also review the main protocols for generating vascularized liver organoids from stem cells and consider their potential and limitations in the generation of vascularized liver organoids. Full article

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14 pages, 4819 KiB

Open AccessArticle

Partial Decellularization for Segmental Tracheal Scaffold Tissue Engineering: A Preliminary Study in Rabbits

by Luong Huu Dang, Yuan Tseng, How Tseng and Shih-Han Hung

Biomolecules 2021, 11(6), 866; https://doi.org/10.3390/biom11060866 - 10 Jun 2021

Cited by 12 | Viewed by 5143

Abstract

In this study, we developed a new procedure for the rapid partial decellularization of the harvested trachea. Partial decellularization was performed using a combination of detergent and sonication to completely remove the epithelial layers outside of the cartilage ring. The post-decellularized tracheal segments [...] Read more.

In this study, we developed a new procedure for the rapid partial decellularization of the harvested trachea. Partial decellularization was performed using a combination of detergent and sonication to completely remove the epithelial layers outside of the cartilage ring. The post-decellularized tracheal segments were assessed with vital staining, which showed that the core cartilage cells remarkably remained intact while the cells outside of the cartilage were no longer viable. The ability of the decellularized tracheal segments to evade immune rejection was evaluated through heterotopic implantation of the segments into the chest muscle of rabbits without any immunosuppressive therapy, which demonstrated no evidence of severe rejection or tissue necrosis under H&E staining, as well as the mechanical stability under stress-pressure testing. Finally, orthotopic transplantation of partially decellularized trachea with no immunosuppression treatment resulted in 2 months of survival in two rabbits and one long-term survival (2 years) in one rabbit. Through evaluations of posttransplantation histology and endoscopy, we confirmed that our partial decellularization method could be a potential method of producing low-immunogenic cartilage scaffolds with viable, functional core cartilage cells that can achieve long-term survival after in vivo transplantation. Full article

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14 pages, 3522 KiB

Open AccessArticle

The Effect of Alendronate on Osteoclastogenesis in Different Combinations of M-CSF and RANKL Growth Factors

by Věra Hedvičáková, Radmila Žižková, Matěj Buzgo, Michala Rampichová and Eva Filová

Biomolecules 2021, 11(3), 438; https://doi.org/10.3390/biom11030438 - 16 Mar 2021

Cited by 9 | Viewed by 2642

Abstract

Bisphosphonates (BPs) are compounds resembling the pyrophosphate structure. BPs bind the mineral component of bones. During the bone resorption by osteoclasts, nitrogen-containing BPs are released and internalized, causing an inhibition of the mevalonate pathway. As a consequence, osteoclasts are unable to execute their [...] Read more.

Bisphosphonates (BPs) are compounds resembling the pyrophosphate structure. BPs bind the mineral component of bones. During the bone resorption by osteoclasts, nitrogen-containing BPs are released and internalized, causing an inhibition of the mevalonate pathway. As a consequence, osteoclasts are unable to execute their function. Alendronate (ALN) is a bisphosphonate used to treat osteoporosis. Its administration could be associated with adverse effects. The purpose of this study is to evaluate four different ALN concentrations, ranging from 10⁻⁶ to 10⁻¹⁰ M, in the presence of different combinations of M-CSF and RANKL, to find out the effect of low ALN concentrations on osteoclastogenesis using rat and human peripheral blood mononuclear cells. The cytotoxic effect of ALN was evaluated based on metabolic activity and DNA concentration measurement. The alteration in osteoclastogenesis was assessed by the activity of carbonic anhydrase II (CA II), tartrate-resistant acid phosphatase staining, and actin ring formation. The ALN concentration of 10⁻⁶ M was cytotoxic. Low ALN concentrations of 10⁻⁸ and 10⁻¹⁰ M promoted proliferation, osteoclast-like cell formation, and CA II activity. The results indicated the induction of osteoclastogenesis with low ALN concentrations. However, when high doses of ALN were administered, their cytotoxic effect was demonstrated. Full article

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34 pages, 39665 KiB

Open AccessArticle

Development of Standardized Fetal Progenitor Cell Therapy for Cartilage Regenerative Medicine: Industrial Transposition and Preliminary Safety in Xenogeneic Transplantation

by Alexis Laurent, Philippe Abdel-Sayed, Aurélie Ducrot, Nathalie Hirt-Burri, Corinne Scaletta, Sandra Jaccoud, Katja Nuss, Anthony S. de Buys Roessingh, Wassim Raffoul, Dominique Pioletti, Brigitte von Rechenberg, Lee Ann Applegate and Salim Darwiche

Biomolecules 2021, 11(2), 250; https://doi.org/10.3390/biom11020250 - 9 Feb 2021

Cited by 10 | Viewed by 3968

Abstract

Diverse cell therapy approaches constitute prime developmental prospects for managing acute or degenerative cartilaginous tissue affections, synergistically complementing specific surgical solutions. Bone marrow stimulation (i.e., microfracture) remains a standard technique for cartilage repair promotion, despite incurring the adverse generation of fibrocartilagenous scar tissue, [...] Read more.

Diverse cell therapy approaches constitute prime developmental prospects for managing acute or degenerative cartilaginous tissue affections, synergistically complementing specific surgical solutions. Bone marrow stimulation (i.e., microfracture) remains a standard technique for cartilage repair promotion, despite incurring the adverse generation of fibrocartilagenous scar tissue, while matrix-induced autologous chondrocyte implantation (MACI) and alternative autologous cell-based approaches may partly circumvent this effect. Autologous chondrocytes remain standard cell sources, yet arrays of alternative therapeutic biologicals present great potential for regenerative medicine. Cultured human epiphyseal chondro-progenitors (hECP) were proposed as sustainable, safe, and stable candidates for chaperoning cartilage repair or regeneration. This study describes the development and industrial transposition of hECP multi-tiered cell banking following a single organ donation, as well as preliminary preclinical hECP safety. Optimized cell banking workflows were proposed, potentially generating millions of safe and sustainable therapeutic products. Furthermore, clinical hECP doses were characterized as non-toxic in a standardized chorioallantoic membrane model. Lastly, a MACI-like protocol, including hECPs, was applied in a three-month GLP pilot safety evaluation in a caprine model of full-thickness articular cartilage defect. The safety of hECP transplantation was highlighted in xenogeneic settings, along with confirmed needs for optimal cell delivery vehicles and implantation techniques favoring effective cartilage repair or regeneration. Full article

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2020

Jump to: 2023, 2022, 2021

15 pages, 11531 KiB

Open AccessArticle

Fallopian Tube Basal Stem Cells Reproducing the Epithelial Sheets In Vitro—Stem Cell of Fallopian Epithelium

by Maobi Zhu, Tomohiko Iwano and Sen Takeda

Biomolecules 2020, 10(9), 1270; https://doi.org/10.3390/biom10091270 - 3 Sep 2020

Cited by 13 | Viewed by 4694

Abstract

The fallopian tube (FT) is an important reproductive organ in females. The luminal epithelium of the FT is composed of highly polarized secretory and ciliated cells. Recently, accumulating lines of evidence have suggested that the origin of high-grade serous ovarian carcinoma (HGSC) is [...] Read more.

The fallopian tube (FT) is an important reproductive organ in females. The luminal epithelium of the FT is composed of highly polarized secretory and ciliated cells. Recently, accumulating lines of evidence have suggested that the origin of high-grade serous ovarian carcinoma (HGSC) is fallopian tube epithelial cells (FTECs). Due to the lack of a high-fidelity model for FTECs in vitro, homeostasis, differentiation, as well as the transformation of FTECs are still enigmatic. In this study, we optimized the culture condition for the stable expansion of basal stem cells, as well as inducing differentiation of basal cells into polarized secretory and ciliated cells in the air–liquid interface (ALI) condition suitable for long-term culture. This storable culture method of FTECs provides a versatile platform for studying differentiation mechanisms, intercellular communication, and transformation to HGSC, as well as the physiological function of the FT in vitro. Full article

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16 pages, 29240 KiB

Open AccessArticle

Extracellular Vesicles from Healthy Cells Improves Cell Function and Stemness in Premature Senescent Stem Cells by miR-302b and HIF-1α Activation

by Cristina Mas-Bargues, Jorge Sanz-Ros, Aurora Román-Domínguez, Lucia Gimeno-Mallench, Marta Inglés, José Viña and Consuelo Borrás

Biomolecules 2020, 10(6), 957; https://doi.org/10.3390/biom10060957 - 25 Jun 2020

Cited by 42 | Viewed by 3816

Abstract

Aging is accompanied by the accumulation of senescent cells that alter intercellular communication, thereby impairing tissue homeostasis and reducing organ regenerative potential. Recently, the administration of mesenchymal stem cells (MSC)-derived extracellular vesicles has proven to be more effective and less challenging than current [...] Read more.

Aging is accompanied by the accumulation of senescent cells that alter intercellular communication, thereby impairing tissue homeostasis and reducing organ regenerative potential. Recently, the administration of mesenchymal stem cells (MSC)-derived extracellular vesicles has proven to be more effective and less challenging than current stem cell-based therapies. Extracellular vesicles (EVs) contain a cell-specific cargo of proteins, lipids and nucleic acids that are released and taken up by probably all cell types, thereby inducing functional changes via the horizontal transfer of their cargo. Here, we describe the beneficial properties of extracellular vesicles derived from non-senescent MSC, cultured in a low physiological oxygen tension (3%) microenvironment into prematurely senescent MSC, cultured in a hyperoxic ambient (usual oxygen culture conditions, i.e., 21%). We observed that senescent MCS, treated with EVs from non-senescent MCS, showed reduced SA-β-galactosidase activity levels and pluripotency factor (OCT4, SOX2, KLF4 and cMYC, or OSKM) overexpression and increased glycolysis, as well as reduced oxidative phosphorylation (OXPHOS). Moreover, these EVs’ cargo induced the upregulation of miR-302b and HIF-1α levels in the target cells. We propose that miR-302b triggered HIF-1α upregulation, which in turn activated different pathways to delay premature senescence, improve stemness and switch energetic metabolism towards glycolysis. Taken together, we suggest that EVs could be a powerful tool to restore altered intercellular communication and improve stem cell function and stemness, thus delaying stem cell exhaustion in aging. Full article

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28 pages, 1411 KiB

Open AccessFeature PaperReview

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

by Manoj Kumar Jena, Neeta Raj Sharma, Matthew Petitt, Devika Maulik and Nihar Ranjan Nayak

Biomolecules 2020, 10(6), 953; https://doi.org/10.3390/biom10060953 - 24 Jun 2020

Cited by 128 | Viewed by 14641

Abstract

Preeclampsia (PE) is a serious pregnancy complication, affecting about 5–7% of pregnancies worldwide and is characterized by hypertension and damage to multiple maternal organs, primarily the liver and kidneys. PE usually begins after 20 weeks’ gestation and, if left untreated, can lead to [...] Read more.

Preeclampsia (PE) is a serious pregnancy complication, affecting about 5–7% of pregnancies worldwide and is characterized by hypertension and damage to multiple maternal organs, primarily the liver and kidneys. PE usually begins after 20 weeks’ gestation and, if left untreated, can lead to serious complications and lifelong disabilities—even death—in both the mother and the infant. As delivery is the only cure for the disease, treatment is primarily focused on the management of blood pressure and other clinical symptoms. The pathogenesis of PE is still not clear. Abnormal spiral artery remodeling, placental ischemia and a resulting increase in the circulating levels of vascular endothelial growth factor receptor-1 (VEGFR-1), also called soluble fms-like tyrosine kinase-1 (sFlt-1), are believed to be among the primary pathologies associated with PE. sFlt-1 is produced mainly in the placenta during pregnancy and acts as a decoy receptor, binding to free VEGF (VEGF-A) and placental growth factor (PlGF), resulting in the decreased bioavailability of each to target cells. Despite the pathogenic effects of increased sFlt-1 on the maternal vasculature, recent studies from our laboratory and others have strongly indicated that the increase in sFlt-1 in PE may fulfill critical protective functions in preeclamptic pregnancies. Thus, further studies on the roles of sFlt-1 in normal and preeclamptic pregnancies are warranted for the development of therapeutic strategies targeting VEGF signaling for the treatment of PE. Another impediment to the treatment of PE is the lack of suitable methods for delivery of cargo to placental cells, as PE is believed to be of placental origin and most available therapies for PE adversely impact both the mother and the fetus. The present review discusses the pathogenesis of PE, the complex role of sFlt-1 in maternal disease and fetal protection, and the recently developed placenta-targeted drug delivery system for the potential treatment of PE with candidate therapeutic agents. Full article

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