Ten kinds of kidney‐nourishing herbs used in clinical treatments.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Traditional Chinese medicine (TCM) is one of the oldest medical treatments in the world. Limited by the times, it is characterized by the Yin‐Yang, Five‐Element, and Zang‐Fu theory. The Zang‐Fu theory explains the physiological function and pathological changes of human body, and the most vital organ would be the kidney. In western medicine, the kidneys are excretory organs with endocrine function. In TCM, it is not only related with anatomical concept but beyond of that. The material basis of kidney essence has long puzzled Chinese scientists. Dysfunction of hypothalamic‐pituitary‐adrenal (HPA) axis [1], hypothalamic‐pituitary‐gonadal (HPG) axis [2], and hypothalamic‐pituitary‐thyroid (HPT) axis [3] have been putting forward proposals. Nowadays, the stem cells self‐control system depending on neuro‐endocrine‐immune (NEI) system regulated microenvironment [4] is the dominant academic view. Moreover, chromosome [5], vitamin D (calcitriol) [6], and erythropoietin (EPO) [7] were also considered to be the material basis of kidney essence. In modern medicine, the kidneys are endocrine organs that secrete a variety of hormones, such as renin [8], kallikreins [9], EPO [10], calcitriol [11], BMP‐7 [12], and klotho [13]. This chapter aims to compare the similarities of the essence of kidney in TCM and the active substance secreting by the kidneys, and to propose the idea that renal endocrine function has the potential to be one of the kidney essence.
Essence (Jing) is the basic substance both constituting the body and supporting its functional activities. The functions of essence are controlling reproduction, growth, and development, promoting the transformation of blood. For example, the forward movement of sperm in infertile men with kidney deficiency was much lower than that in fertile men, and the expression of c‐kit mRNA, a marker of sperm damage, was increased [14]. For female, more than half of premature ovarian failure (POF) patients were differentially diagnosed by TCM as deficiency of kidney in 122 cases [15]. Destruction of the gonad was usually used to induce kidney deficiency animal model. Kidney‐essence deficiency mice showed lower sperm density and motility, and lesser number of baby mice. The same is true for their descendants [16].
\nAccording to Suwen (Plain Questions), a classical work of the TCM theory, kidney essence controls the natural human processes from birth to death. There is an abundance of kidney essence in childhood, which provides the power to grow teeth, hair, and bones. During puberty, the kidney essence is even more plentiful resulting in the ability of fertility. Then female fertility begins to decline after 35 years old and male\'s after 40, as the kidney essence starts to decline. In old age, the kidney essence depletes as time passes, accompanying with infertility, osteoporosis, anemia, baldness, tinnitus, and even hearing loss. Therefore, aging is considered to be physiological kidney deficiency [17].
As urinary organs, TCM kidney and anatomical kidneys both bear consistency of functional. In the rat model of kidney‐yang deficiency, classical kidney‐nourishing formulas strongly regulated the RAA system hormone disorder [18].
According to the TCM theory, kidney controls deep and normal breathing in spite of the difficult‐to‐understand relationship between the kidneys and the lungs. It has been proved that kidney deficiency related closely with stable phase of chronic obstructive pulmonary disease (COPD) [19]. Geng et al. [20] found that the number of asthma attacks of children treated with tonifying qi and kidney TCM significantly decreased, and the effect remained after withdrawal of TCM for 9 months.
Stored in the kidneys, essence can transform into the marrow that fills up the bone cavities, where the blood is produced. The brain is even named as the “sea of marrow.” For this reason, kidney essence is so important for bone development, healthy teeth, blood formation, and normal cognitive function. For example, the risk of fracture is significantly higher in chronic kidney disease (CKD) patients than in the general population [21]. The expenditures of oral problems also increased steadily along with the severity of CKD stages [22]. Homeostasis of calcium and phosphate maintain the development of bones. Many renal endocrines take part in the courses of bone metabolism, such as 1, 25(OH)2D3, Klotho, BMP‐7, and EPO. Aging may increase the risk of kidney dysfunction, and finally results in cardiovascular events, metabolic bone diseases, and even death [23].
\nWhen people are getting old, cognitive problems become more and more evident, such as amnesia, retard response, apathy, agnosia, and depression. The disorder of memory and cognitive deficit are usually related to Alzheimer\'s disease (AD) and vascular dementia (VD). TCM considered that the elderly person initially with kidney deficiency tends to have dementia. Promoting the transformation of blood is another function of kidney essence. Therapy of nourishing kidney [24] could promote the proliferation and differentiation of bone marrow hematopoietic progenitor cells in vitro.
Hair is nourished by the blood, which is generated from essence. Hairs collected from kidney deficiency patients [25] showed the shortest hair diameter and the relatively wide intervals between cuticles. Meanwhile, the levels of trace elements [26] and amino acids [27] in hair of patients with renal diseases decreased.
Presbycusis is regarded as a model of “kidney deficiency” deafness in TCM. The GC/MS analysis showed that hearing loss in the elderly people were positively correlated with kidney deficiency score in TCM [28]. It may be related to glutathione metabolism, amino acid metabolism, glucose metabolism, NMDA receptors, and GABA receptors. In addition, the ear length declined with the diminished kidney function after kidney donation [29].
\nIn summary, the Five‐Element theory serves to categorize all things in nature with the characteristics of five elements (Figure 1). Meridian tropism is used to explain the selectivity of drug action on a part of the body. For example, TCM considered that “salty flavor entering the kidney,” “black food nourishing the kidney,” and “correspondence of kidney with winter.” Modern research has shown that salt is associated with the secretion of renin and the occurrence of high blood pressure. Black rice rich in several anthocyanins are effective in the prevention of hypertension [30].
Categorization of kidney manifestation.
According to the similarities of the kidney endocrine substances and the kidney essence in the sources and functions (Figure 2), we summarize several hormones secreted by the kidneys.
Similarity of kidney endocrine substances and kidney essence.
Renin is produced by renal juxtaglomerular epithelioid cells [8], and its secretion is with salt sensitivity [31]. Renin is believed as the regulators of kidney‐yang, due to its participation in the blood pressure control system. In contrast, kallikrein‐kinin system (KKS), mainly expressed in the distal tubules and collecting ducts of kidney [9], can lower blood pressure and promote the differentiation of stem cells, as the regulator of kidney‐yin. Unlike the two above, EPO is exclusively secreted by renal interstitial fibroblast cells [10], which can regulate differentiation of red blood cells, stem cells, and progenitor cells. It is a veritable substance of nourishing blood. Calcitriol and BMP‐7 are the presentations of the “kidney controls the bones” theory. The former is produced via 25‐hydroxyvitamin D3 1 alpha‐hydroxylase (CYP27B1) in renal proximal tubular cells [11], while the latter is expressed in the renal outer medulla and in glomeruli, and in several glomerular cell types, such as mesangial, epithelial, and endothelial cells [12]. Knocking out BMP‐7 in mice resulted in death shortly after delivery, with kidney failure, skeleton deformity, and eye loss [32].
\nAs one of the material basis of the “kidney stores essence” theory, we will highlight α‐klotho in this chapter. Klotho is mainly expressed in the distal tubule and the collecting duct [13]. As a longevity gene klotho has been widely known, as its reduction directly affects life expectancy [33]. Compared with the wild‐type littermates, serum klotho level is reduced by approximately 80% in mice with renal‐specific deletion of klotho, and exhibited severe growth retardation, kyphosis, and premature death. Serum α‐klotho levels in healthy people rise with age to young adults and then gradually decline while age increased, showing a parabola [34]. The change of α‐klotho level (Figure 3) is consistent with the description of kidney essence in Suwen.
(A) Changes of kidney essence with age according to description of “Suwen.” (B) Serum level of klotho protein changes with the human age [34].
Many studies have shown that α‐klotho deficiency affects bone marrow stem cells and blood cell growth, development, and differentiation [35–37]. α‐Klotho and EPO can be regulated by each other [38, 39]. Obviously, the role of α‐klotho is very similar to the TCM theory of “kidneys essence generating marrow and producing blood.”
\nModern medical research has elucidated that α‐klotho deficiency causes bone matrix protein distribution changes and calcification defect [40]; and participates in calcium and phosphorus metabolism [41]. α‐Klotho also regulates the expression of vitamin D receptor [42]. It is clear that the lack of 1,25‐dihydroxyvitamin D3 can lead to osteoporosis [43]. Studies have shown that the introduction of variant KL‐VS of the human KLOTHO gene in mice enhances cognitive function and increases serum α‐klotho levels [44].
\nIt has also been observed that there is a relationship between klotho and reproductive function [39]. The Nabeshima group also found that klotho‐deficient mice have abnormal regulation of gonadotropins [45]. Recent studies have shown that maternal serum α‐klotho exhibits positive association with fetal birth weight [46]. Our research shows that klotho expression in testis in 30‐week‐old SHR is significantly lower than that of normal controls Wistar‐Kyoto (WKY) rats [47]. At present, although there is no direct evidence to prove the relationship between angiotensin II and klotho in testes, a lot of circumstantial evidence appears that klotho protect the organs and antagonistic effects of angiotensin II [48, 49]. Overall, we find that klotho function and the “kidney stores essence” theory have many overlapping and covering, reflecting the similarities between the two.
There are many successful medical records of diseases treatment through kidney‐nourishing therapy. For a good illustration of the fundamental role of tonifying kidney, as shown in Table 1, we summarize 10 common Chinese medical herbs for tonifying kidney and sum up their pharmacological activities.
Chinese name | Latin name | Medicinal parts | Therapeutic efficacy |
---|---|---|---|
Yin‐yang‐huo (淫羊藿) | Epimedium brevicornu Maxim. | Whole‐herb | To treat impotence and seminal emission, weak and cold and sterile, frequent urination and urinary incontinence, asthma, soreness and weakness of waist and knees, rheumatic arthralgia, hemiplegia, insensitivity of the limbs. |
Bu‐gu‐zhi (补骨脂) | Psoralea corylifolia Linn | Dried fruit | To treat kidney‐deficiency, backache, frequent urination, enuresis in children, leakage of protein or red blood cells in the urine, warming spleen and stopping diarrhea, asthma. |
He‐shou‐wu (何首乌) | Polygonum multiflora (Thunb.) Harald. | Root | To treat light‐headedness hemopenia, palpitation, insomnia, soreness and weakness of waist and knees, premature graying hair, tinnitus, spermatorrhea, constipation due to intestinal dryness, weakness by chronic malaria, rubella itching, carbuncle, scrofulous, hemorrhoids, hyperlipemia. |
Tu‐si‐zi (菟丝子) | Cuscuta chinensis Lam. | Dried seed | To treat impotence and seminal emission, urine dripping after urination, frequent urination and urinary incontinence, soreness and weakness of waist and knees, eyes faint and tinnitus, threatened abortion, embryonic instability, diarrhea caused by deficiency of spleen and kidney, leukoderma. |
Du‐zhong (杜仲) | Eucommia ulmoides Oliver | Dried bark | To treat soreness and weakness of waist and knees, atrophy and weakness of foot and knee, dribble after voiding, genital damp itch, embryonic instability, threatened abortion, hypertension. |
Shu‐di‐huang (熟地黄) | Rehmannia glutinosa | Prepared root | To treat liver and kidney Yin deficiency, soreness and weakness of waist and knees, osteopyrexia and fever, night sweat and spermatorrhea, blood‐deficiency and pale complexion, palpitation, irregular menstruation, uterine bleeding and morbid leukorrhea, vertigo and tinnitus, premature graying hair, intrinsic heat and diabetes. |
Gu‐sui‐bu (骨碎补) | Davallia mariesii Moore ex Bak. | Root and stem | To treat soreness and pain of waist and knees, vertigo and tinnitus, toothache and tooth mobility, injury and broken bones, alopecia areata, leukoderma. |
Xian‐mao (仙茅) | Curculigo orchioides Gaertn | Root | To treat impotence and cold semen caused by kidney‐yang deficiency and yin‐cold excess, urinary incontinence, abdominal cold‐pain, soreness and pain of waist and knees, weak bones and lower limb spasm, menopausal syndrome. |
Suo‐yang (锁阳) | Cynomorium songaricum Rupr. | Succulent stem | To treat soreness and weakness of waist and knees, impotence and spermatorrhoea, constipation due to intestinal dryness. |
Shan‐zhu‐yu (山茱萸) | Cornus officinalis Sieb. et Zucc. | Dried fruit | To treat soreness and pain of waist and knees, vertigo and tinnitus, impotence and spermatorrhoea, frequent urination and urinary incontinence, uterine bleeding and morbid leukorrhea, incessant sweating due to debility, intrinsic heat and diabetes. |
Ten kinds of kidney‐nourishing herbs used in clinical treatments.
2,3,5,4′‐Tetrahydroxystilbene‐2‐O‐β‐D‐glucoside (THSG) is the main composition of Polygonum Multiflorum (Thunb.) Harald., a traditional kidney‐yin reinforcing herb. Our research has showed that THSG inhibited vascular aging [50] and regulated the expression of klotho, especially in the brain, testis, and kidney [47]. It also has the therapeutic benefits in bone diseases. For instance, THSG enhances the bone strength in vivo [47]. It has been reported that kidney‐nourishing herbs improve the metabolism of calcium and phosphorus [51], regulate the levels of estrogen and 1,25‐dihydroxyvitamin D3 [52], and increase the activity of 1‐α hydroxylase in renal disorder diseases [53]. Another kidney‐yang nourishing herb, Epimedium brevicornu Maxim., and its active ingredient icariin can increase the klotho expression in vitro and in vivo [54]. The extract of polysaccharides of Cornus officinalis Sieb. et Zucc. [55] has a similar effect.
\nBavachalcone, one of the effective components of Psoralea corylifolia L., is also a kidney‐yang reinforcing herb. Our results demonstrated that bavachalcone not only prevents endothelial cells senescence [56, 57], but also promotes differentiation of bone marrow stem cells and endothelial progenitor cell via EPO/AMPK pathway (our unpublished data). Effects of kidney‐nourishing herbs on differentiation of bone marrow mesenchymal stem cells also have been reported recently. For example, Epimedium brevicornu Maxim. enhances proliferation and osteogenic differentiation [58]; Davallia mariesii Moore ex Bak. stimulates differentiation into chondrocytes [59]; icariin facilitates differentiation into cardiomyocytes [60]; Rehmannia glutinosa polysaccharides induces the formation of neuron‐like cells or endothelial‐like cells [61]; Curculigo orchioides Gaertn promotes differentiation into neurons [62]; and polysaccharides from Morinda officinalis How. and THSG promotes the proliferation and differentiation of bone marrow stem cells, and increases the number of peripheral blood cells in cancer chemotherapy [63].
\nKidney‐nourishing herbs also display effects of promoting cognitive function in type 1 diabetes and vascular cognitive impairment [64, 65]. Moreover, they successfully support the luteal insufficiency infertility [66]. Animal experiments further confirmed that the nourishing kidney treatment can promote ovulation and ovarian luteinizing hormone receptor expression in infertile rats [67].
Kidney essence declines with aging and leads to a variety of diseases, such as infertility, osteoporosis, senile dementia, aplastic anemia, and senility. Given the importance of kidney essence to life, researchers seek to understand the connotation of the “kidney stores essence” theory. Although “stem cells are congenital essence” is prevailing now, the plausible models and nonspecific indexes still need improvement. The kidney endocrine substances are similar with the kidney essence in their source and functions. It may have some help for the comprehension of the Zang‐Fu theory and point to new targets for antiaging drugs. However, whether the kidney‐nourishing medicine has implications on the kidney endocrine substance, still need further researching and discussing.
In the last decade, we observed a massive upsurge of studies in the field of extracellular vesicles (EVs) [1]. As it is known now, EVs can be loaded with different therapeutic molecules and transport them to recipient cells with little interrogation by the immune system. This property of EVs prompts new possibilities for treatment in various clinical settings [2, 3, 4]. In this chapter, we review the biology of EVs as a universal cellular component from a broader perspective, and afterward provide an updated view on red blood cell extracellular vesicles (RBCEVs), their merits and potential applications in therapeutics [5].
\nWolf was the first to discover small procoagulant structures derived from activated platelets in human blood and named them “platelet dust” in 1967. He separated the small structures by ultracentrifugation and further characterized them using an electron microscopy [6]. In 1987, Johnstone further studied the formation of such vesicles in the duration of sheep reticulocytes maturation in vitro. He was able to identify more activities and characteristics of the vesicles. However, he did not name the small vesicles or discover how they were generated in detail [7]. Both of these findings were important milestones in the field, which allowed for further studies on the function of these small vesicles. Today, we call these small vesicles as EVs. Valadi and colleagues were the first who discovered the natural delivery of microRNAs and mRNAs in EVs in mast cells. Later on, nucleic acid transport via EVs was also observed in many other cell types as an essential manner of intercellular communication [8, 9, 10]. We now have a much more profound understanding in the field of EVs due to the continuous efforts of various scientists throughout many decades.
\nEVs are a heterogeneous class of cell-derived structures with a lipid bilayer membrane, which comprise exosomes, microvesicles, and apoptotic bodies. They are either of the endosomal origins or are shed from the plasma membrane under physiological and pathological conditions. Additionally, they are present in almost all biological fluids, such as blood, urine, breast milk, cerebrospinal fluid, saliva, semen, etc. [11, 12, 13, 14, 15, 16, 17]. Further characterizations are based on the different sizes and biogenesis of EVs. Exosomes generally range from 50 to 150 nm in diameter and are secreted from endosomal multivesicular bodies, whereas microvesicles are larger vesicles ranging from 100 to 500 nm in diameter and are formed through a budding or exocytosis process of the plasma membrane [11, 18, 19, 20, 21, 22, 23]. Apoptotic bodies are much larger, ranging from 800 to 5000 nm in diameter, and are generated by blebbing of plasma membrane from cells undergoing apoptosis. Hence, apoptotic bodies represent the fragments of dying cells and differ from exosomes and microvesicles in property (Figure 1) [17, 18, 19, 20, 21, 22]. In this chapter, we will collectively term both exosomes and microvesicles as EVs with apoptotic bodies excluded.
\nBiogenesis and composition of extracellular vesicles. Extracellular vesicles (EVs) are composed of exosomes, microvesicles, and apoptotic bodies. Exosomes are typically of endosomal origins and are the smallest among them with 50 to 150 nm in diameter. Microvesicles are larger in size from 100 to 500 nm in diameter and are generated through an outward budding or exocytosis of the plasma membrane. Apoptotic bodies are usually the largest ranging from 800 to 5,000 nm in diameter and are generated by blebbing of plasma membrane from cells undergoing apoptosis. Major components of EVs are lipids, proteins, and nucleic acids. Due to different biogenesis mechanisms, the compositions of exosomes and microvesicles do vary.
The components of EVs are mainly proteins, lipids, and nucleic acids. However, due to different biogenesis mechanisms, the compositions of exosomes and microvesicles do vary slightly [11, 24, 25, 26]. Proteins that are associated with endocytic pathways can be usually found in EVs, such as flotillin and annexin. Some of the biogenesis-associated proteins, such as Tsg101 and Alix, and common tetraspanins, such as CD9 and CD81, are commonly used as EVs markers with CD63 which is mostly regarded as a marker of exosomes. However, currently, there lack well-defined protein markers to distinguish exosomes and microvesicles [11, 24, 25, 26]. Lipid components of EVs include phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingomyelin, cholesterol, and so on, which can be found in plasma membrane as well. As microvesicles are formed by budding from plasma membrame, the lipid composition of microvesicles resembles that of plasma membrane of the cells more while exosomes are of higher levels in sphingomyelin, cholesterol, and phosphatidylserine [27, 28, 29]. It is noteworthy that many nucleic acid species are highly enriched in EVs. The lipid bilayer structure of EVs acts as a natural shelter against degrading nucleases in the extracellular environment and protects the nucleic acid cargo under adverse conditions such as long-term storage and multiple freeze-thaw cycles. In the recent decade, reports have it that many mRNAs, microRNAs, and other non-coding RNAs are discovered in EVs (Figure 1) [30, 31, 32].
\nAs EVs are abundant and widely distributed in biological fluids and carry bioactive cargo, they influence various biological processes of the donor and recipient cells [33]. The intercellular communication can occur between cells by transferring EVs that act as an exchange mediator of proteins, lipids, and RNAs. Thus, EVs have a fundamental role to play in important biological processes such as the exchange of surface membrane and horizontal RNA transport between neighboring and remote cells [18]. This aspect is being extensively investigated in cancers [34], neurodegenerative diseases [35], autoimmune disorders [36], aging [37], and so on. The bioactive cargo encapsulated by EVs contain valuable information from the source of diseases, which can serve as robust biomarkers in diagnostics and status snapshots in treatment monitoring [38, 39]. The endogenous property of transporting molecules by EVs inspires researchers to utilize them as a superb delivery platform of therapeutic agents as well [40].
\nSimilar to EVs released from other cells, EVs in the circulation carry biomarkers originated from the donor cells [41]. Usually EVs contain various markers which indicate their origins, e.g., CD235a (also called GPA) for RBCs, CD41 for platelets, and CD11c for dendritic cells [42, 43, 44]. RBCs express classes of CD59 and DAF, known as complement inhibitors, and signaling of CD47 and SHPS-1 molecules on the cell surface to protect themselves against endogenous elimination [45, 46]. For instance, the RBCs membrane protein CD47 inhibits RBCs phagocytosis via macrophages by binding to the inhibitory receptor signal regulatory protein alpha (SIRPα). The presence of such proteins on the surfaces of RBCEVs may help RBCEVs to escape from the clearance by macrophages if they carry CD47 on their surfaces [47, 48, 49]. Mature RBCs lack nuclei and most of the intracellular membrane structures; hence, EVs released from mature RBCs are microvesicles derived from the plasma membrane (Figure 2). Even with the same cell origins, the protein or lipid compositions of EVs may differ on account of the lateral cell membrane variation. Further proteomic assays have illustrated that to some extent, the proteomic spectrum difference of EVs and the releasing cells can be attributed to the stimulating conditions during EVs biogenesis [50]. Microvesicles derived from RBCs are reported to be different in protein contents when produced naturally in vivo, ex vivo released during cold storage of RBCs, or in vitro by treatment with EVs’ release-inducing chemicals such as calcium ionophore, even though they seem homogeneous merely based on their size and/or surface markers. The most distinctively different proteins are stomatin and flotillin-2 [51].
\nUsing red blood cell extracellular vesicles (RBCEVs) for therapeutic delivery. Calcium ionophore is added to RBCs which simulates the release of microvesicles, the only type of RBCEVs. Naturally, RBCEVs contain hemoglobin, Alix, TSG101, and some microRNAs in their lumen. They also display stomatin (STOM) and glycophorin A (GPA) on their membrane. RBCEVs can be loaded with therapeutic molecules including RNAs, proteins, and chemical drugs for delivery of these molecules to other cell types.
There are many studies of RBCEVs under diseased conditions with malaria being frequently reported. Mantel and colleagues illustrated that EVs from human RBCs infected with Plasmodium falciparum parasites contain microRNAs that are able to moderate target genes in recipient cells [52]. The infected RBC-derived EVs in malaria were internalized by endothelial cells and the EVs-encapsulated miRNA-Argonaute 2 complexes repressed miRNA target genes and changed endothelial barrier properties. Furthermore, multiple miRNA species in such EVs were identified [52]. Ankarklev and colleagues reviewed the role of RBCEVs in malaria and found that the development of EVs by Plasmodium sp. is associated with clinical outcomes [53]. Studies have pointed out that elevated EVs levels were detected in patients with severe malaria cases, and increased EV excretion to the endothelium has been linked to infected RBCs [53].
\nChang and colleagues demonstrated the ability of RBCEVs to efficiently deliver ultra-small superparamagnetic iron oxide particles into human bone marrow mesenchymal stem cells for cellular magnetic resonance imaging in vitro and in vivo in order to develop successful stem cell therapies [54]. The novel method overcomes the difficulty of relatively low intracellular labeling efficiency and addresses biosafety issues associated in comparison with traditional approaches. RBCEVs were shown to be ultra biosafe and can be used as potential delivery vehicles for clinical applications due to their autologous property to human bone marrow mesenchymal stem cells [54]. Usman and colleagues developed a robust delivery system for RNA-based therapeutics using RBCEVs [55]. Using the novel RBCEVs delivery platform, both small RNA, e.g., antisense oligonucleotides (ASOs), and large RNA, such as Cas9 mRNA, can be electroporated into RBCEVs and transported to target cells in both solid and liquid tumors. In the study, microRNA-125b-ASO-loaded RBCEVs significantly dampened breast tumor growth by intratumoral injection and suppressed acute myeloid leukemia (AML) progression by systemic administration. Genome editing effects were also observed when RBCEVs were loaded with Cas9 mRNA with guide RNAs. The delivery efficiency was higher and far less cytotoxicity was observed as compared to other commercial transfection reagents [55].
\nUp to now, standardized protocols for EVs isolation for either scientific research or clinical application are lacking [56]. One of the commonly used methods to obtain EVs is ultrafiltration with subsequent differential ultracentrifugation. Ultrafiltration followed by liquid size exclusion chromatography suits the large-scale demand of isolating EV for therapeutics as the method results in, on the one hand, a significantly higher EV yield and, on the other hand, the well-preserved biophysical properties of the purified EVs [57]. Usman and colleagues provided a lab-based approach to purify RBCEVs using ultracentrifugation with sucrose cushion. To begin with, RBCs in whole blood were separated from white blood cells and plasma by low centrifugation and using leukodepletion filters. Then, the isolated RBCs were diluted in PBS and treated with 10 mM calcium ionophore overnight which can stimulate the release of RBCEVs and significantly increase the yield. In order to purify RBCEVs, RBCs and cell debris were removed by several rounds of low-speed centrifugation. Later, the resulting supernatants were passed through 0.45 μm syringe filters. Afterward, the RBCEVs were concentrated using ultracentrifugation at 100,000 × g for 70 min. Subsequently, RBCEVs were resuspended in cold PBS and layered above frozen 60% sucrose cushion and centrifuged at 100,000 × g for 16 h. The red layer of RBCEVs above the sucrose was collected and washed again with cold PBS by ultracentrifugation [55]. The approach is cost-effective, features high RBCEVs yield, and can be adopted in most laboratory settings. The use of sucrose cushion is also a highlight as it helps remove the protein contaminants outside RBCEVs, which might trigger unnecessary immune response and protects the integrity and biophysical properties of RBCEVs.
\nFor therapeutic agents to be loaded into EVs, two major strategies currently have been applied. The first option is to load the therapeutic molecules, such as RNAs, into the EVs after EVs isolation, while the second one is conducted during EV biogenesis. These methods are also known as post-loading and pre-loading, respectively. The pre-loading encapsulation approach is also referred to as the endogenous method as it uses the cellular machinery in order to load small RNA into EVs. The pre-loading approach has been shown to work for the packaging of both siRNA and miRNA into EVs. The post-loading method artificially introduces RNAs into EVs, whereas pre-loading is performed in the EVs biogenesis. Post-loading can be subdivided into passive loading, such as by physical incubation, and active loading with instances of electroporation or sonication. Furthermore, the functional small RNAs delivery using electroporated EVs has been shown to be a success in several reports but it depends on the small RNA species [58, 59, 60, 61, 62]. Usman and colleagues used the electroporation method for post-loading of RNAs into RBCEVs [55]. Ideally, various therapeutic molecules including ASOs, siRNAs, gRNAs, mRNAs, plasmid DNA, proteins, peptides, and chemical drug compounds can be loaded into RBCEVs using electroporation (Figure 2). Other post-loading methods such as mild sonication and physical incubation may be applicable to RBCEVs as tested for other types of EVs. Labeling of EVs is then required to examine the efficiency of delivery to target cells. Various methods and techniques have been applied to label EVs, with most common methods being incubation with biotinylated radioisotope, substrate of luciferase, fluorescence lipophilic dye, streptavidin-conjugated fluorescence dyes, or the use of other modified proteins [55, 64, 65, 66].
\nDue to their innate function on cell-cell communication, EVs can be used effectively for drug delivery [12, 67, 68, 69]. The biggest advantage of EVs drug delivery is probably that EVs can be taken from an organism and returned to the same organism in vivo after being loaded with therapeutic agents, which are thought to be nonimmunogenic. Another advantage to deliver nucleic acids with the help of EVs is that EVs can carry molecules through physiological barriers, such as the blood-brain barrier, which are hard to cross using conventional delivery methods. Normally, when exogenous RNAs are introduced into the body directly, they will be cleared before reaching the target tissues or cells of interest through degradation by nucleases, or they will be filtered in the kidneys. Both coding and noncoding RNAs were shown to be transferred by EVs intercellular crosstalks. Additionally, it has been shown that microRNAs can be transported in EVs to various cell types. Thus, EVs can be used as a promising vehicle for delivery of RNA-based drugs. Potential fields for therapeutic use include gene therapy, targeted therapy, vaccination, improvement of pregnancy outcome, newborn medicine, kidney disease, and treatment of autoimmune disease [12, 67, 68, 69].
\nIt has been reported that diversified types of cells, including RBCs, endothelial cells, monocytes, granulocytes, and platelets, release EVs. Additionally, EVs can be isolated by various methods from cell culture media, plasma, and other biofluids [23, 41, 70, 71]. Although several research groups have demonstrated the advantages of using EVs for RNA delivery, there are still issues with EVs generated from fibroblasts and dendritic cells being not permanently available from all subjects [69, 72]. RBCs are readily obtainable from any human subject and easy to store, and blood transfusion has been a relatively safe, well-established, and routine medical procedure for decades which makes RBCEVs easy to obtain and safe to use. Thus, EVs from whole plasma are easily accessible and substantially present, but these EVs are derived from various cell types, e.g., nucleated cells which represent a risk for horizontal gene transfer [63]. Therefore, obtaining ultrapure RBCEVs solely derived from RBCs is highly preferred as RBCs lack both nuclear and mitochondrial DNA, which means that RBCEVs for pharmaceutical purpose avoid the risk of horizontal gene transfer. RBCEVs formation has been extensively investigated and described in the recent years. Therefore, with such knowledge, RBCEVs are safer and less complicated to use [73, 74, 75, 76].
\nConsequently, RBCEVs possess several features which make them better suitable for clinical applications than EVs from other cell types. First of all, blood units are easily accessible from existing blood banks. A large scale of RBCEVs can be produced at low cost as RBCs are the most abundant cell type in the body (84% of all cells) and, during their 120-day lifespan, RBCs continue to release RBCEVs, leading to an approximate 20% loss in RBCs volume and an increase of around 14% in hemoglobin concentration [23, 77, 78, 79]. Additionally, RBCEVs are obtainable for allogeneic and autologous transfusion from the patients’ own blood. A large number of RBCs (~1012 cells/L) are obtainable from each blood unit. Thus, there exists no need to expand cells in culture and no risk of the emergence of mutations in vitro. In addition, no cGMP-qualified media or supplements are required, which are financially desirable. Large-scale amounts (1013–1014) of RBCEVs can be isolated from RBCs (per unit) when treated with calcium ionophore, which is a scalable strategy to obtain EVs. Secondly, RBCEVs are safer compared to EVs from other cell types, because the enucleated RBCs contain no DNA, unlike EVs from nucleated cell types which represent a potential risk for horizontal gene transfer. As plasma EVs are heterogeneous with unpredictable contents, RBCEVs are safer than plasma EVs for allogeneic treatments of cancer because cancer cells and immune cells are known to release large amounts of cancer-promoting EVs into their environment [80, 81]. Thirdly, RBCEVs are nontoxic; hence, they are safer as compared to the toxic synthetic transfection reagents which are typically used. As mentioned before, RNAs in RBCEVs are stable and completely functional in vitro and in vivo for both liquid and solid cancers. Fourthly, RBCEVs are presumably nonimmunogenic via blood type matching, unlike adenoviruses, adeno-associated viruses, lentiviruses, nanoparticles, and various synthetic transfection reagents. Last but not least, RBCEVs can be frozen and thawed many cycles without affecting their integrity or efficacy. This fact suggests that RBCEVS can be developed into stable pharmaceutical products in the future, but further research needs to be done. Compared to most other current methods for programmable RNA drug therapies, which are unsuitable for the clinical use because of the low uptake efficiency and high cytotoxicity, RBCEVs show promising future prospects [55].
\nEVs are shed from the plasma membrane or released by endosomal pathways under both physiological and diseased conditions. Intercellular communication is one of the best known functions of EVs by far, which provides the possibility to utilize the EVs natural vehicle property of transporting nucleic acids, proteins, and lipids for drug delivery. Recent studies demonstrate that human RBCEVs can be developed as robust delivery platform for multiple therapeutic RNAs in cancer treatment. RBCEVs feature multiple benefits as compared to EVs from other cell types. They are easily obtainable in large amounts, can be frozen and thawed multiple times without significant compromise, are nontoxic and nonimmunogenic, can reach remote tissues in the body with minimal hindrance by physiological barriers, and do not contain DNA or other unpredictable contents which could result in horizontal gene transfer. By obtaining RBCEVs directly from the patient, they are safe to use allogeneic treatments and possess no risk of emerging mutations during expansion by cell culture. Thus, RBCEVs show promising advantages in overcoming various limitations of cell-based therapeutics. All in all, RBCEVs need further research in order to establish them as a new source and promising approach for practical therapeutics in clinical use.
\nWe would like to thank our colleagues at City University of Hong Kong including Chin Siew Mei, Waqas Muhammad Usman, Tin Chanh Pham, Luyen Tien Vu, Boya Peng, Thach Tuan Pham, Abdullah Faqeer, Yeokyeong Kim, Seongkyeol Kim, Likun Wei, Ching Yee Moo, Ru Zhen, and Migara Kavishka Jayasinghe for their support. We are grateful to the generous funding from the Hong Kong Health, and Medical Research Fund (grant 03141186) and the Hong Kong Research Grants Council (grant 21106616).
\nThe authors declare no conflict of interest.
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