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REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 109-122

Functions of lysosomes in mammalian female reproductive system


1 Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA
2 Department of Physiology and Pharmacology, College of Veterinary Medicine; Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602, USA

Date of Submission26-Feb-2020
Date of Decision06-May-2020
Date of Acceptance20-May-2020
Date of Web Publication26-Jun-2020

Correspondence Address:
Xiaoqin Ye
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, 501 DW Brooks Drive, Athens, GA 30602; Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.288025

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  Abstract 


The lysosome is the most acidic membrane-bound intracellular organelle. Lysosomal acidity is primarily maintained by vacuolar H+-ATPase (V-ATPase) and counter ion channels. There are >60 hydrolytic enzymes in the lysosome for its fundamental digestive role. Lysosomes also play important roles in endocytosis, exocytosis, autophagy, and cell death. Studies that have implicated roles of lysosomes in the female reproductive system are reviewed here. In the ovary, lysosomes are implicated in the preparation of free cholesterol for steroidogenesis and degradation of regulators of steroidogenesis, regulation of follicular atresia, follicle rupture during ovulation, luteal cell survival, and luteal regression. In the oviduct, lysosomes are involved in endocytosis of both serum and oviductal luminal components. In the uterus during the menstrual/estrous cycle, lysosomes are associated with endometrial secretion, apoptosis, and menstruation. In the uterus during early pregnancy, lysosomes are involved in the temporal and directional changes of endocytosis, uterine epithelial acidification upon embryo implantation initiation, and embryo-maternal mutual communications via extracellular vesicles. In the placenta, lysosomes are implicated in nutrient transport and placental separation from the uterus for parturition. In the mammary gland, lysosomes are important for mammary gland development and involution. These findings suggest/demonstrate functions of lysosomes in multiple processes of female reproduction, from ovulation to ovarian steroidogenesis for pregnancy maintenance, and from essential in utero nurturing of developing embryos/fetuses via embryo/fetal-maternal communications, to optional postpartum nurturing of newborns via lactation. Future studies using genetically or modified animal models and pharmacological approaches will provide novel insights into the functions and mechanisms of lysosomes in the mammalian female reproductive system.

Keywords: Autophagy; Endocytosis; Lysosome; Ovary; Steroidogenesis; Uterus


How to cite this article:
Li Y, Wang Z, Andersen CL, Ye X. Functions of lysosomes in mammalian female reproductive system. Reprod Dev Med 2020;4:109-22

How to cite this URL:
Li Y, Wang Z, Andersen CL, Ye X. Functions of lysosomes in mammalian female reproductive system. Reprod Dev Med [serial online] 2020 [cited 2020 Sep 20];4:109-22. Available from: http://www.repdevmed.org/text.asp?2020/4/2/109/288025




  Introduction Top


The lysosome was first described and named by the Belgian cytologist and biochemist De Duve et al. in 1955.[1] It is the most acidic membrane-bound intracellular organelle, with a lumen pH of ~4.5–5.0. This environment is optimal for >60 different hydrolytic enzymes in the lysosome, such as proteases (e.g., cathepsins), lipases, nucleases, glycosidases and phosphatases, that can break down biomolecules within intracellular and extracellular origins. Lysosomal acidity is primarily maintained by vacuolar H+-ATPase (V-ATPase) to pump H+ into the lysosomal lumen and counter ion channels to dissipate the transmembrane voltage built up by V-ATPase.[2] In addition to its digestive role, the lysosome is also important for intracellular trafficking, cellular homeostasis, metabolic signaling, cholesterol transport, lipid metabolism, immune response, and hormonal signaling, etc.[2],[3],[4],[5],[6] Mutations in lysosomal genes could potentially lead to lysosomal dysfunction. Disrupted lysosomal functions in degradation, export, or trafficking can lead to abnormal accumulation of lysosomal materials, resulting in >50 rare inherited metabolic disorders in humans, collectively termed lysosomal storage diseases.[7] The lysosome participates in essential cellular processes such as endocytosis and exocytosis [Figure 1], autophagy [Figure 2], and cell death [Figure 3].
Figure 1: Four main types of endocytosis and a proposed exocytosis involving lysosomes. (A) Clatherin-mediated endocytosis. (B) Clatherin-independent endocytosis. (C) Pinocytosis. (D) Phagocytosis. (E) A few events involving endocytosis in the female reproductive system. (F) A proposed lysosomal exocytosis. (G) A few events potentially involving exocytosis in the oviduct and uterus. Part of the figure was created using BioRender.

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Figure 2: Three types of autophagy. (A) Macroautophagy. (B) Chaperone-mediated autophagy. (C) Microautophagy. (D) A few events involving autophagy in the female reproductive system. Part of the figure was created using BioRender.

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Figure 3: The lysosome and cell death. (A) Involvement of lysosomes in different types of cell death, including lysosome-dependent cell death. (B) A few events involving lysosome-dependent cell death in female reproduction. Part of the figure was created using BioRender.

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Endocytosis transports extracellular cargo molecules to the lysosome for processing. There are four main types of endocytosis [Figure 1]A, [Figure 1]B, [Figure 1]C, [Figure 1]D: clathrin-mediated endocytosis,[8] clathrin-independent endocytosis,[9] pinocytosis,[10] and phagocytosis.[11] The involvement of lysosomes in exocytosis is relatively less studied and the mechanisms involved are still under investigation. Lysosomes and lysosome-related organelles can be transported to and fused with the plasma membrane to release the lysosomal contents into the extracellular space. Increased intracellular calcium level and depletion of cholesterol can both trigger lysosomal exocytosis, which is a tightly regulated process involving microtubules and actins, Rab GTPases, and SNAREs,[12] [Figure 1]F.

Autophagy delivers unwanted intracellular cargo molecules, which could be of extracellular origin, to the lysosome for degradation and nutrient cycling.[13] There are three main types of autophagy [Figure 2]A, [Figure 2]B, [Figure 2]C: macroautophagy, chaperone-mediated autophagy, and microautophagy. The primary type of autophagy is macroautophagy. It requires the formation of autophagosomes [Figure 2]A that involves LC3/MAP1LC3 (microtubule-associated proteins 1A/1B light chain 3B, cytosolic form LC3-I, membrane form LC3-II). Autophagosomes fuse with lysosomes to form autolysosomes for cargo degradation by lysosomal hydrolases. Many genes, such as autophagy-related (ATG) genes, have been identified to play essential roles in the autophagic pathways and implicated in the functions of the female reproductive tract.[13]

There are generally two types of cell death, regulated cell death and accidental cell death. Lysosome-dependent cell death [Figure 3] is a type of regulated cell death,[14] in which lysosomal membrane permeabilization causes selective release of cathepsins or massive release of lysosomal enzymes leading to cell death. It could also trigger other types of regulated cell death, such as apoptosis and pyroptosis, which is a highly inflammatory form of programmed cell death in which cathepsins are involved.[15]

The mammalian female reproductive system generally consists of two ovaries, two fallopian tubes/oviducts, a uterus/two uterine horns, a placenta/placentas, a cervix, a vagina, and mammary glands. During the years following the discovery of the lysosome, studies dating back to 1973 revealed the presence of lysosomes and/or the activities of lysosomal enzymes in the ovary, uterus, cervix, and vagina using electron microscopy and biochemical approaches. Many of these studies were previously reviewed.[16],[17] Since then, more studies in different species have implicated lysosomes in the female reproductive system, but have not been comprehensively reviewed. This review updates the research on the functions and mechanisms of lysosomes in the female reproductive system. It will be organized roughly based on the order of female reproductive organs involved in the pregnancy process: ovary, oviduct, uterus, placenta, parturition, cervix and vagina, and mammary gland [Figure 4].
Figure 4: Summary of known or suggested functions of lysosomes in the female reproductive tract. (A) Fallopian tube (oviduct). (B) Uterus. (C) Placenta. (D) Vagina. (E) Mammary gland. Part of the figure was created using BioRender.

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  Functions of Lysosomes in the Ovary Top


The ovary is an essential part of the hypothalamic-pituitary-ovarian (HPO) axis connecting the central nervous system and the female reproductive system [Figure 5]. The ovary contains primary oocytes, developing follicles, atretic follicles, interstitium, and corpus luteum (corpora lutea, plural). It is the site for oocyte maturation. Although lysosomes do not seem to have a substantial presence in the oocyte, they play an essential role in follicle atresia, ovulation, luteal regression, luteal cell survival, and ovarian steroidogenesis [Figure 6].
Figure 5: Functions of lysosomes in the HPO axis and steroidogenesis. (A) Female reproductive system, including the ovary, fallopian tube/oviduct, uterus, placenta (not shown), cervix, and vagina. The female reproductive system is under the control of HPO axis. After puberty, the releasing of GnRH from hypothalamus will bind to GnRH receptor on anterior pituitary to stimulate the secretion of FSH and LH. During follicular phase, the FSH binds to FSH receptor on granulosa cells to induce estrogen (E2) synthesis. Meanwhile, LH binds to LH receptor on theca cells to induce the synthesis of androgens, which will be transferred to granulosa cells for E2synthesis. E2will have negative feedback on LH and FSH secretion (B). During follicular phase, E2causes proliferating effects on the endometrium of the uterus (A). During pre-ovulation, on the other hand, E2will accumulate and have positive feedback on the LH and FSH secretion, which will lead to ovulation (C). After ovulation, the granulosa cells and theca cells will differentiate into lutein cells in the corpus luteum. Similar as in the follicle phase, granulosa lutein cells and theca lutein cells also receive LH and FSH signaling from the anterior pituitary. The main difference is the high level production of progesterone (P4), which is stimulated by LH acting on both granulosa and theca lutein cells. P4 and E2will send negative feedback for LH and FSH secretion (D). The combination of E2and P4 from corpus luteum will induce secretory effects on the endometrium of the uterus (A). Lysosomes (pink vesicles) are shown to regulate steroidogenesis in the preparation of free cholesterol, the substrate for steroidogenesis, as well as in the degradation of LH and LHR and FSH and FSHR to control HPO axis in regulating steroidogenesis in the ovary. HPO: Hypothalamic-pituitary-ovarian; GnRH: Gonadotropin-releasing hormone; LH: Luteinizing hormone; FSH: Follicle-stimulating hormone; LHR: Luteinizing hormone receptor; FSHR: Follicle-stimulating hormone receptor; E2: Estradiol; P4: Progesterone. This figure was created using BioRender.

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Figure 6: Functions of lysosomes during ovarian cycle. Ovarian cycle is a series of changes in the ovary, from oogonium, to primordial follicle and a few more stages, to Graafian follicle, and corpus luteum after ovulation. Most follicles will be removed before reaching Graafian follicles via follicular atresia. Only a few follicles can fully develop from primordial follicles to Graafian follicles, continue with ovulation and corpus luteum formation to go through the full ovarian cycle. Lysosomes have known or suggested functions in follicular atresia, ovulation, luteal maintenance and luteal regression, and steroidogenesis in the ovary. Part of the figure was created using BioRender.

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Lysosomes and hypothalamic-pituitary-ovarian axis

The key hormones in the HPO axis include gonadotropin-releasing hormone (GnRH) from the hypothalamus, luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary, and estrogen and progesterone from the ovary [Figure 5]. Lysosomes were detected in the GnRH neurons of juvenile monkey hypothalamus.[18] Increased volume fraction of lysosomes/lipofuscin was detected in the GnRH neurons of aged female rats.[19] Lysosomes had morphological changes in response to LH-releasing hormone (LH-RH) injections[20] and were involved in the internalization of LH-RH antagonist in the LH gonadotrophs of female rats,[21] suggesting potential functions of lysosomes in regulating LH production.

Studies have shown lysosomal responses, especially activities of lysosomal enzymes, to LH and FSH and their analogs in the ovary. LH and FSH can reduce lysosomal cathepsin D activity in rat granulosa cells of the preovulatory follicles.[22] Equine chorionic gonadotropin/pregnant mare serum gonadotropin (eCG/PMSG) can change the activities of acid phosphatase, N-acetyl-beta-D-glucosaminidase and beta-glucuronidase in the follicular fluid, granulosa and theca cells of preovulatory follicles of immature Wistar rats.[23] PMSG and human chorionic gonadotropin induced superovulation in immature rats is accompanied with increased acid phosphatase activity in granulosa and theca cells of Graafian follicles.[24]

Lysosomes and ovarian follicle atresia

Follicles are the functional units in the ovary. Most of them contain an oocyte surrounded by granulosa cells and in later stages also theca cells lining up the outer layer. They develop from primordial follicles to Graafian follicles (preovulatory follicles) prior to ovulation. In mammals, the majority of follicles are removed by atresia during follicle development. Follicular atresia is a hormonally controlled degenerative process initiated with the death of granulosa cells and ended with the degeneration of oocytes. It was indicated in ewes that the large atretic antral follicles showed more lysosomal rupture in granulosa cells than the small ones. Correspondingly, necrosis appeared to be more dominant in the granulosa cells of large atretic follicles, while apoptosis was more prevalent in the granulosa cells of small atretic follicles.[25] The role of lysosomes in follicular atresia is evolutionarily conserved as cathepsin D-mediated apoptosis in the clearance of follicular cells during follicular atresia is also observed in Nile tilapia.[26]

Oocyte atresia involves autophagy and apoptosis. Since lysosomes are important for both events [Figure 2] and [Figure 3], it was not surprising to find a high number of active lysosomes and autophagolysosomes accompanied with increased activity of lysosomal enzymes in oocytes that were undergoing atresia. It is proposed that the degeneration of oocyte started with autophagy, which can then trigger the apoptosis pathways to degrade nuclear components and remove the cytoplasmic components.[27]

Lysosomes and ovulation

After follicle maturation, a few selected Graafian follicles will undergo ovulation to release the oocytes. Ovulation is a complexed process that involves neuroendocrine regulation, communications among multiple cell types, extensive extracellular matrix remodeling of follicular apex, loss of the surface epithelium, and eventually follicle rupture and oocyte release.[28] During ovulation, there was an increased concentration of lysosomal enzymes in the rat ovarian bursa fluid.[29] It was also observed that the lysosomes from the epithelium covering the Graafian follicles would aggregate into groups and fuse with each other right before ovulation in the rabbit. They would move to the plasma membrane and release the lysosomal enzymes into the extracellular space expectedly to assist follicle rupture during ovulation.[30] These observations suggest the involvement of lysosomes in ovulation.

Lysosomes and luteal regression

Upon ovulation, the oocyte with cumulus cells are released from the mature follicle, while the granulosa and theca cells in the remaining ruptured follicle will differentiate into luteal cells to form a corpus luteum.[31] The corpus luteum is a temporary endocrine structure that is the main site for progesterone production during early pregnancy in some species, and throughout the pregnancy for other species. Progesterone is an essential hormone to support pregnancy. If pregnancy does not occur or another organ takes over progesterone production during pregnancy, the corpus luteum will undergo luteal regression/luteolysis. Luteal regression is associated with increased number and size of lysosomes, as well as increased activities of lysosomal enzymes in bovine, porcine, and mouse corpora lutea.[32],[33],[34] Autophagy, apoptosis, and necrosis have been suggested as mechanisms for lysosomal involvement in corpus luteum regression.[32],[35] Prostaglandin F2alpha (PGF2α), an inducer of luteal regression in domestic animals, can increase the release and activities of lysosomal enzymes, therefore accelerate the regression of corpus luteum.[36] It is not surprising that a KEGG pathway analysis of primate luteal transcriptome revealed differential expression of genes in “lysosome” category between rescued and regressing corpora lutea.[37]

Lysosomes and luteal cell survival

Although it may seem to contradict the role of lysosomes in luteal regression, our recent study suggests a novel role of lysosomes in luteal cell survival.[38] TRPML1 (transient receptor potential cation channel, mucolipin subfamily, member 1, encoded by mucolipin 1 (MCOLN1, Mcoln1)) is an important lysosomal counter ion channel. Mutations in the mucolipin 1 gene can lead to a lysosomal storage disorder called MLIV (Mucolipidosis Type IV) in both humans and mice, which share common clinical features, such as impaired vision, paralysis, and elevated plasma gastrin.[2],[39] MLIV patients do not reproduce[40] but the mechanism of their infertility is unknown. TRPML1 is highly expressed in mouse luteal cells. TRPML1 deficiency in mice led to infertility in 5–6 months old Mcoln1-/- female mice, accompanying with progesterone deficiency and luteal cell degeneration during early pregnancy.[38] Because TRPML1 is required for efficient fusion of autophagosomes with lysosomes, TRPML1 deficiency leads to impaired fusion of autophagosomes with lysosomes for degradation and subsequent accumulation of autophagosomes, which could lead to degenerative cell death in Mcoln1-/- mice and MLIV patients.[39] Extensive luteal cell vacuolization in the Mcoln1-/- corpus luteum most likely represented autophagic vacuoles that were also observed in the Mcoln1-/- gastric epithelial cells[39] and possibly represented spaces of accumulated lipid droplets as well.[38] Since TRPML1 deficiency is related to mitochondrial fragmentation that could contribute to progressive cell degeneration, and there is reduction of mitochondrial marker HSP60 in Mcoln1-/- corpora lutea, Mcoln1-/- luteal cell degeneration could be contributed by both defective lysosomes and defective mitochondria.[38] Because of the essential role of TRPML1 for lysosomal functions, this study in the Mcoln1-/- mice suggests a novel role of lysosomes in luteal cell survival.[38]

Lysosomes and ovarian steroidogenesis

Lysosomes have multiple roles in ovarian steroidogenesis, which is controlled by the HPO axis [Figure 5] and [Figure 6]. The steroid hormones are produced from the common precursor, cholesterol. The main source of cholesterol is through endocytosis of cholesterol rich low-density lipoprotein (LDL) or selective uptake of cholesterol esters from high-density lipoprotein and a minor source is through de novo cholesterol synthesis.[41] A major role of lysosomes in steroidogenesis is to liberate LDL-embedded cholesterol derived from endocytosis.[42] Lysosomal liberation of cholesterol involves lysosomal enzymes and two Niemann-Pick Type C (NPC) proteins: NPC1, a lysosomal membrane protein responsible for exporting free cholesterol, and NPC2, a small and soluble protein binding to cholesterol in the lysosome lumen. NPC1 deficiency leads to female infertility with impaired ovarian function, including impaired ovarian steroidogenesis, caused by defective hypothalamic control of the pituitary in the HPO axis.[43] NPC2 is mainly detected in the theca cells of large and healthy antral follicles, as well as in the luteal cells of the corpora lutea. NPC2 deficient female mice were infertile as they failed to ovulate. They had normal LH and FSH levels but reduced serum estrogen level and increased ovarian cholesterol level, suggesting defective cholesterol export from intracellular stores in the ovarian steroidogenic cells.[44] Lysosomes are also involved in the degradation of regulators of steroidogenesis in the ovary, such as LH-LHR[45] and FSH-FSHR complexes,[46] and intrinsic receptors for PGF2α.[47] In addition to roles in the preparation and transport of the substrate cholesterol and degradation of regulators of steroidogenesis, lysosomes may also have a role in luteal cell survival for steroidogenesis in the corpus luteum.[38]


  Functions of Lysosomes in the Oviduct Top


The oviduct (or fallopian tube in humans) consists of four segments: infundibulum, ampulla, isthmus, and utero-tubal junction. Early pregnancy events, including acrosomal exocytosis, fertilization, early embryo development, and embryo transport towards the uterus, occur in the oviduct.

Studies have shown the presence of lysosomes and lysosomal enzymes in the oviduct. Many primary lysosomes and secondary lysosomes were detected in the nonciliated epithelial cells of sheep oviductal isthmus during early pregnancy.[48] Lysosomes in the oviductal epithelial cells, mainly at the preampulla segment, are involved in the uptake of serum immunoglobulins or intravenously injected tracers (e.g., horseradish peroxidase [HRP] and ferritin) via basolateral endocytosis, and possibly in the digestion of the cargoes (e.g., tracers) during mouse pregnancy.[49],[50] The injected tracers were also detected in apical vesicles of the mouse oviductal epithelial cells, most likely for releasing into the oviductal lumen via exocytosis, in which the role of lysosomes was previously unknown.[50] A proteomics study revealed several lysosomal enzymes in the bovine oviductal fluid, suggesting the participation of lysosomes in the apical secretion of oviductal epithelial cells.[51] The functions of lysosomal enzymes in the oviductal lumen remain to be investigated. Lysosomal enzyme uteroferrin, which is an iron-containing lysosomal acid phosphatase, was detected in the ampulla and isthmus epithelial cells of both cycling and pregnant pigs. Since uteroferrin did not seem to be secreted into the oviductal lumen but uterine lumen,[52] it suggested different vesicle trafficking systems and/or different roles of uteroferrin in the oviduct and uterus. These observations suggest general roles of lysosomes in oviductal epithelium for vesicle trafficking and nutrient recycling.


  Functions of Lysosomes in the Uterus Top


The uterus is the only viable place for a mammalian embryo/fetus to grow to term. The uterine endometrium includes uterine luminal epithelium (LE), glandular epithelium, stromal cells, endothelial cells, and immune cells. It is under the control of ovarian hormones estrogen and progesterone, and undergoes dynamic changes during the menstrual cycle/estrous cycle and pregnancy. Lysosomes have been implicated in the dynamic changes in the endometrium.

Lysosomes and cycling uterus

A female menstrual cycle includes: proliferative phase, secretory phase, and menstruation. Early studies revealed increased lysosomal activities in the glandular epithelium during secretory phase, which may contribute to the enhanced secretion from glandular epithelium during secretory phase and imply a role of lysosomes in exocytosis. Macrophages are phagocytic immune cells that play important roles in the uterus during menstrual/estrous cycle and pregnancy.[53] They are enriched with lysosomal enzymes, such as acid hydrolases. They disappeared in the secretory endometrium and reappeared upon the onset of menstruation, most likely to provide their phagocytic function in which the lysosomes are necessarily involved.[17] Progressively increased autophagy and apoptosis in human endometrium from early proliferative phase to late secretory phase were shown by the expression of MAP1LC3A-II and cleaved caspase 3, respectively.[54] This study further demonstrated the involvement of lysosomes in autophagy and apoptosis in cultured human endometrial cells.[54] These observations imply cell type specific roles of lysosomes in the human endometrium during menstrual cycle.

Lysosomes and lysosomal enzymes in the uterus are responsive to different treatments. The lysosomes in the uteri of Wistar rats can sequester aluminum nitrate and indium sulfate, implying lysosomal function in the defense of xenobiotics.[55] PMSG treatment in immature Wistar rats induced the activities of beta-glucosaminidase and acid phosphatase activities but not that of beta-glucuronidase in the endometrium.[23] Progesterone treatment in ovariectomized rabbits upregulated the activities of a few lysosomal hydrolases, including acid and alkaline phosphatases and beta-galactosidase, in the endometrium.[56] These observations suggest lysosomal functions in uterine defense of xenobiotics and uterine response to hormones.

Lysosomes and uterine endocytosis and secretion

The uterus and its enclosed uterine lumen undergo dynamitic changes in sizes and contents. Endocytosis and exocytosis play important roles in these dynamics[57] and the lysosome has functions in both processes [Figure 1].

Lysosomes are involved in the temporal and directional changes of endocytosis in the mouse uterine epithelium during early pregnancy. On both 0.5 days postcoitus (D0.5) and D4.5, 2 h after intravenous injection, the injected HRP tracer was localized in endocytic vesicles along the basolateral membranes, multivesicular bodies and elongated dense bodies (both of which were positive with lysosomal acid phosphatase), and many small vesicles near the apical surface of the cells. The HRP may be excreted into the uterine lumen and/or digested in the lysosomes. On the other hand, when the HRP was injected into the uterine lumen on these days for 20-40 min, there was no detectable uptake of HRP from the lumen into LE or glandular epithelium on D0.5, but a large amount of HRP was taken up from the uterine lumen into apical endocytic vesicles, multivesicular bodies and dense bodies (lysosomes) in both LE and glandular epithelium on D4.5[58] [Figure 7]. Similar as in mice, LE endocytosis of tracers from uterine lumen during peri-implantation was also observed in rats (using HRP or ferritin as tracers)[59] and rabbits (using labeled uteroglobin as a tracer).[60] Extensive early studies demonstrated that LE apical endocytosis, indicated by the uptake of tracer(s) injected into the uterine lumen, was upregulated by progesterone in both mouse and rat, and peaked around the time of the establishment of uterine receptivity for embryo implantation.[59]
Figure 7: Proposed functions of lysosomes in endocytosis and exocytosis of uterine LE during early pregnancy in mice. (A) On 0.5 days postcoitus (D0.5). Based on (Tung et al. 1988), 2 h after intravenous injection of a tracer HRP, HRP was detected in the endocytic vesicles along the basolateral membrane, multivesicular bodies, and lysosomes, as well as vesicles near the LE apical surface. HRP could be degraded in lysosomes or released to the uterine lumen. Endocytosis of HRP injected into the uterine lumen did not occur in the LE on D0.5. (B) On D4.5 (~D4 12 h). It is ~ 12 h after embryo attachment and ~ 8 h before trophoblast penetration through the LE in mice. Increased endocytosis of intravenous injected HRP was detected in the basolateral LE compared to D0.5. HRP injected into the uterine lumen could be detected in the LE vesicles, indicative of apical endocytosis on D4.5 (Tung et al. 1988). LE vesicle trafficking could deliver messages from the maternal side to the embryo, and vice versa. Extracellular vesicles, including exosomes derived from multivesicular bodies in LE and trophoblasts, are newly recognized players in the maternal-embryo communications that had been demonstrated in sheep.[71] Part of the figure was created using BioRender. HRP: Horseradish peroxidase; LE: Luminal epithelium.

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Lysosomal enzymes can be secreted into uterine lumen under certain circumstances. One example is uteroferrin, a lysosomal acid phosphatase. It is upregulated by progesterone and secreted by uterine epithelium during estrous cycle and pregnancy in pig.[52] Although uteroferrin is a lysosomal enzyme, its secretion into uterine lumen may not involve the lysosome per se because it could be secreted before being targeted to the lysosomes.[61] It was suggested that uteroferrin may carry/transport iron from the uterus to the conceptus for fetal development.[52],[61]

Lysosomal enzymes have dynamic activities in the uterine lavage fluid of nonparturient, postpartum, and ovariectomized postpartum mares.[62] In nonparturient uterine lavage fluid, acid phosphatase, beta-glucuronidase (B-Gase), and N-acetyl-beta-D-glucosaminidase (NAGase) had increased activities in mid-and late-diestrus than in mid- to late-estrus. In 1–4 days postpartum uterine lavage fluid, the activities of acid phosphatase, B-Gase, and NAGase were high but declined rapidly thereafter. These activities were progesterone-dependent. They tended to be higher in the uterine lavage fluid of intact mares than in ovariectomized ones on day 16 postpartum.[62] These findings indicate dynamic endometrial lysosomal secretory activities, which are under hormonal control and are likely associated with endometrial remodeling during estrous cycle and postpartum.

Uterine epithelial acidification upon embryo implantation

An early study implied a more acidic intralysosomal pH in the rat uterine epithelium upon embryo implantation.[63] When nonspecific acid phosphatase activities towards substrates beta-glycerophosphate and p-nitrophenyl phosphate at both pH = 5.0 and pH = 6.0 were evaluated in rat uterine epithelium, it was found that at late diestrus and D5.5 (post-implantation initiation), a significantly larger lysosomal population in the LE and glandular epithelium was operating at pH = 5.0 rather than pH = 6.0; while at estrus, the epithelial lysosomes showed no preference for an operational pH = 5.0 or 6.0. In addition, LE lysosomes had a substrate preference for p-nitrophenyl phosphate over beta-glycerophosphate on D5.5 but not at estrus or late diestrus.[63] D5.5 LE also had increased lysosomal population and more active lysosomes with frequent invaginated or vesiculated forms compared to LE of nonpregnant rats.[63] These observations suggest dynamic changes, including intralysosomal pH, in LE lysosomes upon embryo implantation.

Our microarray analysis of the peri-implantation mouse LE revealed dramatic upregulation of Atpase, H+ transporting, lysosomal V0 subunit D2 (Atp6v0d2),[64] a gene encoding a tissue-specific d subunit of V-ATPase. V-ATPase regulates extracellular lumen pH (when it is located on plasma membrane) and pH in acidic intracellular organelles (when it is located on intracellular organelle membrane), such as lysosomes. This microarray study led us to the novel finding of uterine epithelial acidification during implantation initiation,[65] detected by LysoSensor Green DND-189 (pKa ~5.2). Since the lysosome is the most acidic intracellular organelles within the pH range (pH <5) detectable by LysoSensor Green DND-189, the uterine epithelial acidification detected by LysoSensor Green DND-189 indicates lysosomal acidification, although acidification of other intracellular organelles couldn't be ruled out. Uterine epithelial acidification also occurred in the artificially induced decidualization mouse uterus,[65] indicating the involvement of maternal factors in regulating this process. We further demonstrated that uterine epithelial acidification was associated with uterine receptivity: V-ATPase inhibitor bafilomycin A1 suppressed/delayed uterine epithelial acidification and embryo implantation in a natural pregnancy mouse model as well as uterine preparation for embryo implantation in an artificially induced decidualization mouse model using uterine fat pad injection.[65] However, the detailed mechanisms of how this acidification affects implantation require further investigation.

Lysosomes and embryo implantation

Successful embryo implantation requires synchronized communications between a receptive uterus and a competent blastocyst, and is associated with dynamic changes in the endometrium.[57] For example in mice, uterine fluid has to be reabsorbed for uterine lumen closure to facilitate embryo attachment to the LE (~D4.0); sequential changes take place in the mouse endometrium during the early hours of embryo attachment: blue dye reaction (~D4, 0 h; there is increased vascular permeability at the site of embryo attachment), local edema of the uterine stroma, downregulation of progesterone receptor in the uterine epithelium, and decidualization (~D4, 6 h).[57],[66]

Early studies (reviewed in[17]) indicated that changes at the implantation site were induced entirely by the enzymatic alterations in the endometrium itself, which was based on little evidence of any significant quantity of hydrolytic enzymes secreted by the trophoblasts in both rats and humans. This could be supported by some similar changes in the endometrium of pseudopregnant rodents (e.g., local edema) induced by artificial decidualization and “predecidual reaction” in the secretory phase of the human menstrual cycle. Although there were inconsistent reports, dynamic presence of lysosomes and activities of lysosomal enzymes (e.g., increased acid cathepsin activity) were detected in the endometrium leading to the establishment of a receptive uterus. In addition, lysosomal enzymes β-glucuronidase and acid cathepsin D were shown to have >3 fold increase of activities in the regressing decidual tissues that were no longer needed, suggesting their involvement in controlling the physiological tissue remodeling during pregnancy.[17] A study of D6.5 mouse implantation site revealed increased number of lysosomes and lysosomal enzymes from nondecidualized stromal cells, to predecidual cells, to mature decidual cells, and to dying decidual cells (involution),[67] suggesting the involvement of lysosomes in the differentiation of endometrial stromal cells into decidual cells and involution of the antimesometrial decidua to accommodate embryo development and placental development.

Spatiotemporal studies confirm the association of lysosomal enzymes with the implantation process. Cathepsin D activity increased in the rat LE during early pseudopregnancy and reached maximal levels at the time of sensitivity to deciduogenic stimuli. This upregulation depended on progesterone but not estrogen, which was demonstrated in ovariectomized rats.[68] One study reported increased activity of acid phosphatase and increased number of lysosomes in the LE and glandular epithelium in D5.5 compared to that in the nonpregnant uterus in rats.[69] Another study revealed increased activity of lysosomal arylsulfatases B and acid phosphatase, but not cathepsin B, in the implantation sites compared to the inter-implantation sites ~48 h after embryo attachment, suggesting that the changes were likely associated with the decidualization process, but the localization of increased enzyme activities in the implantation sites was not determined in this study.[70]

Microarray of D3.4 and D4.5 mouse LE (implantation initiates ~D4.0 in mice) showed high levels of expression and/or differential expression of mRNAs encoding lysosomal enzymes (e.g., cathepsins) and lysosomal membrane proteins (e.g., V-ATPase subunits, counter ion channels, and lysosomal associated membrane proteins, etc.) in the LE upon implantation initiation. The cathepsins with the highest expression were cathepsin b (Ctsb) and cathepsin d (Ctsd), while the most highly upregulated cathepsin in D4.5 LE was cathepsin c (Ctsc). Atp6v0d2 was the most highly upregulated V-ATPase subunit in D4.5 LE, and Mcoln1 was among the highest expressed counter ion channels. Both Lamp1 and Lamp2 (lysosomal associated membrane protein-1 and 2) had high levels of mRNA expression in the D3.5 and D4.5 LE with higher expression of Lamp2 than that of Lamp1.[64]

Extracellular vesicles (EVs) are lipid bilayer-enclosed particles (e.g., exosomes and microvesicles) released from cells into extracellular spaces. It has been demonstrated in sheep that uterine epithelial cells can uptake conceptus-derived EVs in vivo.[71] Fusion or endocytosis are the principal mechanisms for uptake of EVs in the cell. Although the mechanisms for the uptake of conceptus-derived EVs in the uterine epithelium were not specifically examined in the study, labeled conceptus-derived EVs were consistently observed as distinct particles or groups of particles, suggesting endocytosis mechanism for the uptake of EVs in uterine epithelium.[71] Lysosomes can affect the fate of the EVs, e.g., sequestered, degraded, or excreted via exocytosis.[72] On the other hand, uterine epithelial cells also secrete EVs that could be detected in the uterine intraluminal fluid. These EVs could enter conceptus trophoblasts, most likely also via endocytosis.[71] These observations indicate a critical role of lysosomes in the embryo/fetal-maternal mutual communications [Figure 7]B.

Lysosomes and embryo penetration at implantation site

In mammals with a hemochorial placenta (humans, mice, etc.) or an endotheliochorial placenta (dog, cat, etc.), the embryo has to penetrate through the LE at the implantation site for successful implantation and subsequent pregnancy. There are species differences in the process of trophoblasts passing through the LE to reach the decidual cells during embryo implantation (https://www.trophoblast.cam.ac.uk/Resources/enders). In rodents, the LE cells surrounding the blastocyst are phagocytosed by protrusions of invading trophoblasts at ~D4 20 h in mice and ~D5 9 h in rats,[73],[74] implying the involvement of lysosomes in the trophoblasts for phagocytic LE removal.

Role of luminal epithelium lysosomes in contraception

Lysosomes have been shown to respond to contraceptive devices (e.g., nonhormonal intrauterine device) and pills (steroidal or nonsteroidal). One study revealed that intrauterine copper wire adversely affected the rabbit blastocysts and LE. It was proposed that in the blastocysts, the entry of copper into the lysosomes caused the release of lysosomal enzymes, cellular autolysis, and death of the affected cells, eventually death of the blastocysts; and in the LE, the uptake of copper led to autophagy and formation of myeloid bodies in the lysosomes, and eventually the shedding of LE.[75] Lysosomes in the rat LE were also shown to respond to centchroman (or ormeloxifene, a nonsteroidal contraceptive and a selective estrogen receptor modulator).[76] The adverse effects of contraceptive tools on the lysosomes in the blastocysts and/or LE inevitably lead to blocking of embryo implantation to achieve contraception. One study on patients with endometriosis showed that prior to treatment, there were small lysosomes in the glandular epithelium, while after the treatment with anti-progesterone steroid R 2323 (Gestrinone, a potential emergency contraceptive), there were darkly stained, heterogeneous autophagic vacuoles, indicating enhanced activity of the lysosomal system in the glandular epithelium.[77] These observations suggest functional involvement of lysosomes in hormonal and nonhormonal contraception.


  Functions of Lysosomes in the Placenta Top


Lysosomal cathepsins have species specific spatiotemporal expressions in the placentas. For example, in human placentas, cathepsin B (CTSB) is predominantly expressed in placental and decidual macrophages, while cathepsin L (CTSL) levels are highest in a subpopulation of invasive cytotrophoblasts. Altered cathepsin expression levels were detected in pre-eclamptic placentas, suggesting roles of cathepsins during normal placentation and in the etiology of pre-eclampsia.[78],[79] In sheep placentas, CTSB, CTSD, and CTSZ mRNAs were predominantly detected in the chorion of the placenta, while CTSL and CST3 (cystatin C, an inhibitor of lysosomal cysteine proteases) proteins were mainly detected in the intercaruncular endometrial glands and intercotyledonary placenta during later pregnancy in sheep.[80] In the pig placenta, CTSB, CTSL1, and CST3 mRNA expression levels increased in the endometrial epithelium during pregnancy.[81] The spatiotemporal expression of cathepsins suggests potential roles of lysosomal enzymes in nutrient recycling for successful utilization, nutrient transport to support fetal development, as well as endometrial remodeling and placentation.

Pigs have noninvasive epitheliochorial placentas; therefore, the nutrients from the maternal endometrium have to be transferred through the LE. During pregnancy from gestation days 16 to 112 in pigs, the LE developed an extensive lysosomal system, especially during the last two-thirds of gestation, consisting of irregular electron-dense bodies, membrane whorls and transfer tubules. These observations suggested that the lysosomal system in the LE facilitated cellular digestion/nutrient preparation to accommodate the fetal development.[82] Lysosomes and lysosomal enzymes, such as uteroferrin, are implicated in maternal-fetal nutrient transport for fetal development.[52],[61]

Autophagy, in which the lysosome plays an essential role [Figure 2], has been implicated in placentation (reviewed in[13],[83]). LC3A and LC3B, which participate in autophagosome formation, have dynamic spatiotemporal expression in the murine D11.5-D15.5 placentas, with significant higher expression levels in the decidual basalis than in the labyrinth zone. ATG7 is an important protein for autophagy. Atg7-deficiency in mouse trophoblasts led to smaller placentas with shallow trophoblast invasion and failure of vascular remodeling. Altered autophagy in the placenta has been associated with pregnancy complications, such as gestational diabetes mellitus and gestational hypertension.[13],[83]

A case study also confirmed an important function of lysosome in the placenta. Mucopolysaccharidosis (MPS) type VII is an inherited lysosomal storage disease caused by the deficiency of lysosomal enzyme β-glucuronidase. An MPS type VII carrier patient (heterozygous) had an affected MPS type VII fetus. Therefore, the fetal side of the placenta was homozygous while the maternal side of the placenta is heterozygous. At 18 weeks of pregnancy, the chorionic villus (fetal side) showed foamy intracytoplasmic vacuoles with a weakly electron-dense substrate.[84] The same patient previously had an affected baby who was born with normal height and weight (but did not survive long after birth), suggesting the plasticity of the placenta, which can accommodate the expected pathological changes in the fetal side of the placenta during the previous pregnancy.


  Functions of Lysosomes in Parturition Top


Uterine transition from quiescence to contraction and the separation of the placenta from the uterus are required for a natural parturition. Different mechanisms have been proposed from myometrial perspective, decidual perspective, fetal membrane perspective, and neuro-immune-endocrine perspective. Although the mechanisms involved in parturition are far from fully understood, these above mentioned aspects could be all involved.[85],[86]

There is evidence demonstrating a role for lysosomes in parturition. Prior to parturition at the end of gestation, decidua and metrial gland will undergo regression to prepare for placenta separation in rats. Strong activities of lysosomal enzymes were detected in cells of both tissues before parturition, suggesting that lysosomes may be involved in decidua and metrial gland regression to facilitate placenta separation during parturition.[87] Lysosomes are also implicated in inflammation-induced preterm labor but not noninflammation (hormonally)-induced preterm labor in mice. In inflammation-induced preterm labor, there was an accumulation of LC3B paralogues and reduction of LAMP-1, LAMP-2, and the a2 isoform of V-ATPase in mouse uterus and placenta, indicating altered autophagic flux in which lysosomes play an important role.[88]


  Functions of Lysosomes in Cervix and Vagina Top


Lysosomes and activities of lysosomal enzymes were detected in the cervix and vagina, especially in the epithelial cells.[16],[89] Deficiency of autophagy gene ATG5 in mouse vaginal cells can impair the clearance of C. albicans infection, implying lysosomes in the host defense of vaginal infection in vivo.[90] In addition, 2 weeks of continuous administration of high daily doses of lipidosis-inducing drugs was shown to overburden the lysosomes in the vaginal epithelium, which were filled with undigested polar lipids. This observation indicates a role of lysosomes in lipid metabolism in the vaginal epithelium.[89] In ovariectomized rats, estrogen treatment increased the release and activity of lysosomal enzymes in the vaginal epithelium, in which the lysosomal enzymes may be responsible for the cornification and detachment of vaginal epithelium.[91]


  Functions of Lysosomes in Mammary Gland Top


In female reproduction, the ultimate role of mammary glands is to produce milk for nursing the offspring. The mammary gland undergoes cyclic changes including development, lactation and involution. At puberty, estrogen induces mammary gland development. During pregnancy, estrogen and progesterone coordinately promote the continuous development of mammary alveoli to prepare for lactation. After parturition, prolactin and oxytocin regulate milk synthesis and secretion from mammary alveoli. Upon weaning of the offspring and cessation of lactation, the mammary glands undergo involution.[92]

Early studies in rodents suggested potential roles of lysosomes in mammary glands. Although there were discrepancies in different studies, a relative consist observation was peaked lysosomal enzyme activities during mammary gland involution ([93],[94] and their citations). An electron microscopy study revealed shifts in lysosomal populations (primary, secondary, casein-positive, and dense body) in the mammary epithelial cells during differentiation/pregnancy, secretion/lactation, and involution, suggesting active roles of lysosomes in mammary glands throughout different stages.[94]

Recent studies have demonstrated functions of lysosomes in mammary gland development, producing milk components and mammary gland involution [Figure 3]B and [Figure 4]E. V-ATPase is essential for regulating lysosomal pH. Mouse mammary glands deficient of the a2 subunit (a2V) of V-ATPase had impaired development, accompanied with disrupted endolysosomal route in Notch and TGF signaling, which plays a major role in mammary gland development.[95] Although not in lactation per se, lysosomes function in producing milk components, such as cholesterol, an important lipid component in milk. Lysosomes have a fundamental role in regulating cellular cholesterol homeostasis.[42] Lysosomal cholesteryl ester hydrolase activity was dramatically increased in the lactating rat mammary gland compared to the virgin counterpart.[96] Impaired lactation in a2V-deficient mouse mammary gland might be a secondary effect of impaired mammary gland development.[95] Lysosome-dependent cell death [Figure 3] is a hallmark of mammary gland involution. It is activated by upregulation of lysosome biogenesis and acidification, a process involving Zinc transporter 2 (ZnT2 [SLC30A2]),[97] proceeds with lysosomal membrane permeabilization and leakage of intralysosomal components (e.g., cathepsins). Mouse models have revealed signal transducer and activator of transcription 3 (STAT3)[98] and calpains[99] in regulating this process. The trigger for STAT3 involvement is the uptake of milk fat globules, which are delivered to lysosomes to cause lysosomal membrane permeabilization; the involvement of STAT3 may also be contributed by its upregulation of cathepsins B and L, which will be among leaked cathepsin proteases.[98] Calpains, on the other hand, proteolyze lysosomal membrane proteins to cause lysosomal membrane permeabilization.[99]


  Future Prospects Top


Since the identification of lysosomes in 1955, tremendous progress has been made with respect to understanding the functions and mechanisms of lysosomes in eukaryotic cells. Novel functions and mechanisms of lysosomes are continuously being uncovered. Lysosomes have a spatiotemporal presence in the female reproductive system, as well as in the HPO axis that regulates the functions of the female reproductive system. Relative to the progresses in understanding the lysosome in some other systems, such as the nervous system, the progresses in understanding the lysosome in the female reproductive system are lagging behind. The importance of lysosomes can be reflected in lysosomal storage disorders, which comprise a group of at least 50 distinct genetic diseases that affect about 1 in 7,000 of newborns.[100] Genetically modified animal models that mimic lysosomal storage disorders could provide invaluable insights into the functions of lysosomes in the female reproductive system. Since the acidic environment in the lysosome is maintained via V-ATPase and counter ion channels for proper lysosomal functions, and lysosomal enzymes are main contributors for lysosomal functions, pharmacological approaches modifying the activities of V-ATPase, counter ion channels, and/or lysosomal enzymes could be employed for studying the functions of lysosomes in the female reproductive system. Because the female reproductive system is under the control of HPO axis, it is important that any potential functions of lysosomes in the hypothalamus and pituitary are also considered when the function (s) of lysosomes in the female reproductive system are being investigated. Cellular functions of lysosomes are being revealed in different cells of the female reproductive system, while the molecular mechanisms involved are emerging. These are a few directions for studying functions and mechanisms of lysosomes in the female reproductive system.

Financial support and sponsorship

We thank the financial support from Interdisciplinary Toxicology Program, Department of Physiology and Pharmacology, College of Veterinary Medicine, and Office of the Vice President for Research at University of Georgia, as well as the National Institutes of Health (R01HD065939 (co-funded by ORWH and NICHD), R03HD097384, and R03HD100652).

Conflicts of interest

There are no conflicts of interest.



 
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