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. 2026 Oct 15;405(3):14. doi: 10.1007/s00441-026-04098-x

Cells for blastema formation: Lessons from the annelid regenerative model

Toshiyuki Fujita 1, Shinji Yamaguchi 1,✉
PMCID: PMC13672576  PMID: 42878876

Abstract

Regeneration in many animals involves the formation of blastema, a mass of undifferentiated, proliferating cells. The origin of blastema cells is a key question in regenerative biology. Two major theories are: (1) the migration of lineage-restricted stem cells, supported by studies in salamanders and planaria, and (2) the dedifferentiation of somatic cells at the injury site, which has been observed in newts, mice, zebrafish, and crickets. Because different models support these theories, the generality of either mechanism is unclear. To address this, these theories should be investigated in a wider range of regenerative model animals. To this end, Fujita et al. (2024) studied the regenerative annelid Enchytraeus japonensis and discovered that soxC-expressing cells are crucial for blastema formation. In this review, we introduce an annelid model system for regeneration biology and the roles of soxC-expressing cells during blastema formation.

Keywords: Blastema, Annelid, Regeneration, Wnt, SoxC, Stem cell, E. japonensis, Crosstalk

Introduction

When an animal loses a body part, such as a limb or tail, it may be possible to reconstitute the missing parts (regeneration). This type of regeneration is referred to as epimorphic regeneration, proceeding through several major steps after amputation: wound healing, blastema formation, and regenerative outgrowth. A blastema is a mass of undifferentiated, proliferating cells that provides the foundation for the regeneration of body parts (Barresi and Gilbert 2019; Poss 2010; Sanchez Alvarado and Tsonis 2006). Blastema formation is one of the most critical steps during this type of regeneration (Barresi and Gilbert 2019; Poss 2010; Sanchez Alvarado and Tsonis 2006). In the blastema, various cellular processes, such as cell proliferation, cell fate determination, and axis formation, are coordinated through signaling pathways shared with developmental processes (Bely and Nyberg 2010; Srivastava 2021). For example, regenerative genetic studies in zebrafish have proposed that canonical Wnt signaling regulates multiple signaling pathways and indirectly regulates cell proliferation during the early phase of regeneration (Wehner et al. 2014; Wehner and Weidinger 2015). Knowledge regarding the signaling pathways that play important roles in regeneration, including blastema formation has been accumulated across various model systems, such as fish (Poss 2010; Riley et al. 2022; Shibata et al. 2016; Wehner and Weidinger 2015), amphibians (Maden 2007; Saito et al. 2019; Yokoyama et al. 2001) and mammals (Plikus et al. 2011), as recently reviewed by (Bangru et al. 2025). An important issue regarding blastema formation is the cell sources of blastema (Tanaka and Reddien 2011).

There are two major blastema cell source theories. The first is that lineage-restricted stem cells migrate to the amputation site. For example, in vertebrate regeneration models, studies using lineage-tracing tools have found that certain connective tissue progenitors migrate to the amputation site and contribute to blastema formation during limb regeneration in salamanders (Currie et al. 2016) and fin regeneration in zebrafish (Tornini et al. 2016), after wound healing. In planaria, using transplantation and partial irradiation, a study indicated that stem cells are mobilized to sites of injury (Guedelhoefer and Sanchez Alvarado 2012). Several studies in planaria indicated that cell migration is crucial for blastema formation (Abnave et al. 2017; Lapan and Reddien 2011). The second theory is that somatic cells at the amputation site dedifferentiate. For example, in zebrafish, mature osteoblasts dedifferentiate and form part of the blastema of the caudal fin (Knopf et al. 2011). In limb regeneration of newt, somatic cell labelling of muscle fibers using Cre/loxP showed that muscle fibers dedifferentiate into progenitor cells as blastema source cells that contribute to regenerated muscle (Sandoval-Guzman et al. 2014). In murine digit tip regeneration, lineage tracing with single-cell profiling indicates that endogenous osteoblasts or osteocytes acquire a blastema mesenchymal transcriptional state and contribute to both dermis and bone regeneration (Storer et al. 2020). In cricket leg regeneration, injury-induced dedifferentiated cells proliferate and form blastema (Bando et al. 2018). However, it remains unclear whether these cell source theories for the blastema can be generally applied among broad animal species. To resolve this issue, these theories should be verified in other model animals.

Recently, using the highly regenerative annelid Enchytraeus japonensis Fig. 1a, Fujita et al. (2024) revealed that Sry-related high-mobility group box (sox)C-expressing cells play a pivotal role in blastema formation. In this review, we outline and discuss recent findings focusing primarily on soxC-expressing cells during blastema formation. Several excellent reviews are relevant and complementary to the content covered here, including information on regenerating tissues and the regenerative process as a whole. We point readers to reviews on the cellular basis of regeneration in animals such as planarians, Hydra, zebrafish, and amphibians (Tanaka and Reddien 2011), the molecular and cellular basis for limb regeneration in salamanders (Tanaka 2016), the molecular and cellular basis for annelid regeneration (Bely 2014; Kostyuchenko and Kozin 2021; Ozpolat and Bely 2016), stem cells and the evolution of whole-body regeneration (Gehrke and Srivastava 2016), signalings during tissue regeneration in adult invertebrate and vertebrate model animals (Bangru, et al. 2025).

Fig. 1.

Fig. 1

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Enchytraeus japonensis as a regeneration model animal. (a) A photo depicting E. japonensis. (b) Phylogenetic position of annelids used as regeneration models. Species included in this figure are some of most commonly studied in the recent literature and do not represent all annelid species studied to date. (c) Blastema formation in E. japonensis. When transversely amputated, E. japonensis completes blastema formation within 24 h, achieving full regeneration within 4 d. (d) In annelids, three regions have been proposed as potential stem cell niches: the posterior growth zone (PGZ) near the tail tip, where new segments are generated; the gonads in segments seven and eight; and putative pluripotent stem cells (neoblasts) located ventrally in contact with septa separating body segments

Enchytraeus japonensis as a regeneration model animal

Many annelids have high regenerative abilities and species such as Pristina leidyi (freshwater annelid), Capitella teleta (marine annelid), Platynereis dumerilii (marine annelid) have been widely used as model annelids for studying regeneration (Ozpolat and Bely 2016) Fig. 1b. In some annelids, pharmacological inhibition using small-molecule inhibitors has been applied to investigate the function of key signaling pathways. For example, Wnt/β-catenin signaling has been studied during regeneration in Capitella teleta (Kunselman and Seaver 2025), Aeolosoma viride (Chen et al. 2022; Chen et al. 2020; Fok et al. 2020), and Lumbriculus variegatus (Tellez-Garcia and Arellano-Carbajal 2025), as well as during development in Platynereis dumerilii (Demilly et al. 2013; Schneider and Bowerman 2007; Steinmetz et al. 2007; Zidek et al. 2018). Because all these pharmacological studies employed the soaking method, signaling studies in annelids offer the advantage of a technically simple approach while still being conducted in living organisms. Enchytraeus japonensis (potworm) is an annelid species first reported in Japan in 1993 (Nakamura 1993) and has since been developed as an experimental model for regeneration research (Fujita, et al. 2024; Fujita and Yamaguchi 2026; Kawamoto et al. 2005; Miyachi et al. 2005; Myohara 2004; 2012; Myohara et al. 2006; 1999; Niva et al. 2008; Ogawa et al. 2017; Sugio et al. 2008; 2012; Tadokoro et al. 2006; Takeo et al. 2008; 2010; Yoshida-Noro et al. 2000; Yoshida-Noro and Tochinai 2010). In the laboratory, E. japonensis can be easily maintained on agar plates at 24 °C with powdered oatmeal as a food source. Its body length is approximately 1 cm, facilitating easy handling Fig. 1. Upon maturation, it reproduces asexually by fragmenting its body, although sexual reproduction can also be induced under specific culture conditions (Myohara et al. 1999). The body surface is whitish and semitransparent, permitting direct observation of internal structures including the brain, pharynx, testes, ovaries, intestine, and ventral nerve cord. Following transverse amputation, E. japonensis rapidly closes the wound through contraction of the circular muscles, and wound healing occurs within 12 h (Yoshida-Noro and Tochinai 2010). E. japonensis then completes blastema formation within 24 h and full regeneration within 4 d Fig. 1c. In E. japonensis, pharmacological inhibition using small-molecule proteinase inhibitors reduced blastema size, demonstrating the effectiveness of this approach (Fujita et al. 2024). Additionally, functional genetic approaches using RNA interference (RNAi) for investigating gene function during blastema formation in annelids have only been established in E. japonensis (Nikanorova et al. 2020; Ozpolat and Bely 2016; Takeo et al. 2010). The first RNAi study in E. japonensis employed microinjection of double-stranded RNA (dsRNA) (Takeo et al. 2010) and subsequently, gene-silencing system utilizing soaking or feeding with dsRNA were developed (Fujita et al. 2024). Notably, RNAi-mediated gene silencing produced phenotypes identical to those obtained with protease inhibitors (Fujita et al. 2024). The soaking RNAi approach is particularly advantageous, providing an easily applicable, reproducible, and minimally invasive method for inducing gene knockdown in E. japonensis. Recent studies have indicated that Wnt signaling plays an important role in blastema formation in annelids (as shown in the next section), while our understanding of the mechanism by which canonical Wnt signaling interacts with other signaling pathways remains limited in annelids. Enchytraeus japonensis serves as a powerful model system for investigating the molecular basis of blastema formation, including the required signaling pathways.

Search for the molecular basis of blastema formation in E. japonensis

Transcriptomic approaches have been applied to regeneration blastema to elucidate the cellular and molecular basis of blastema formation in annelids (reviewed in (Kostyuchenko and Kozin 2021)). Because isolating blastema tissue by dissecting small animals such as E. japonensis is difficult, Fujita et al. (2024) applied a strategy in which worms were cut into multiple fragments to enrich blastema in the samples (Fujita et al. 2024). In this study design, three groups were prepared: one divided into eight fragments, one divided into three fragments, and one left intact. The comparison of de novo transcriptome analysis (0 h postamputation [hpa] versus 24 hpa) revealed 278 genes (differentially expressed genes, DEGs) that were upregulated in the eight-fragment group compared with those in the three-fragment group Fig. 2. Notably, Wnt5 and LRP8 were included among the identified DEGs (Fujita et al. 2024) Fig. 2b. These genes are involved in canonical Wnt signaling (Clevers and Nusse 2012; Hu et al. 2024). LRP5 and LRP6 were not included in the DEG list (Fujita et al. 2024), despite their known roles as typical co-receptors in Wnt signaling in vertebrates. LRP8 was included in the list, which was identified as a positive factor of canonical Wnt signaling pathway in murine osteoblast differentiation (Zhang et al. 2012). These findings indicated that the Wnt signaling pathway is active during blastema formation in E. japonensis. This was consistent with recent findings that Wnt/β-catenin signaling specifies posterior identity of marine annelid C. teleta (Kunselman and Seaver 2025). In addition, delta homolog 2 and TGF-β receptor type 3 were also included among these DEGs (Fujita et al. 2024) Fig. 2b. In the Notch signaling pathway, the Delta ligand on a sending cell binds to the Notch receptor on a receiving cell (Kopan and Ilagan 2009). These findings also indicated that the Notch and TGF-β signaling pathways are also activated.

Fig. 2.

Fig. 2

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A model for blastema formation in E. japonensis. (a) soxC-expressing cells (shown in magenta) are potentially supplied to the amputation site. soxC-expressing cells play key roles in blastema formation. vasa1-expressing cells are shown in orange. (b) soxC and signaling pathways genes were upregulated (0 hpa vs. 24 hpa). (c) Clarifying the relationship between soxC-expressing cells and Wnt signaling during blastema formation will provide important insights into the overall architecture of the complex crosstalk orchestrated by canonical Wnt signaling

soxC-expressing cells as a cellular basis of blastema formation in E. japonensis

Transcription factors that act early in regeneration often establish and maintain cell identities (Goldman and Poss 2020). Among the identified DEGs, the most strongly upregulated transcription factor was a member of the SOXC subfamily; this gene was designated Ej-soxC (hereafter referred to as soxC) (Fujita et al. 2024) Fig. 2b. Functional analysis using RNAi assessed whether soxC is involved in blastema formation. Soaking-based RNAi reduced blastema size and markedly decreased cell number. These findings indicated that soxC is required for blastema formation (Fujita et al. 2024).

In situ hybridization (ISH) analysis revealed dynamic changes in soxC expression during blastema formation. Immediately after amputation, soxC-expressing cells were not detected. By 3 hpa, soxC-expressing cells appeared near the body wall adjacent to the wound site. At 5 hpa, soxC-expressing cells were observed at the anterior and posterior wound sites and showed gradual accumulation at these wound sites. At 24 hpa, soxC-expressing cells occupied the majority of the blastema region. Notably, soxC-expressing cells located near the body wall exhibited a flattened and spread morphology, a characteristic feature of migratory cells (Bretscher 2008; Zattara et al. 2016). These findings suggested that soxC-expressing cells adjacent to the body wall may represent migratory cell populations contributing to blastema formation (Fujita et al. 2024) Fig. 2a.

Cellular dynamics during blastema formation in E. japonensis

In annelid, the blastema includes proliferative cells (Planques et al. 2019; Seaver and de Jong 2021) and is considered a mass of unpigmented, undifferentiated cells with high proliferative activity that forms at the wound site (Bely 2014; Ozpolat and Bely 2016). Notably, germline multipotency program (GMP) genes are expressed in the blastema of annelids (Kostyuchenko and Kozin 2021; Ozpolat and Bely 2016; Planques, et al. 2019) as in other model animals (discussed in the following section), potentially representing a general molecular feature of annelid regeneration (Nikanorova, et al. 2020; Ozpolat and Bely 2016; Seaver and de Jong 2021). Cell counting via DAPI staining and pulse–chase analysis using EdU revealed distinct temporal phases of blastema formation. Up to 8 hpa, a certain number of cells were detected at the wound site but little cell proliferation was observed. By 24 hpa, however, a large number of cells had accumulated at the wound site, with approximately 60% having incorporated EdU, indicating active proliferation. These findings strongly suggested that the cells present at the wound site at 8 hpa were not generated through proliferation but were instead supplied from elsewhere (Fujita et al. 2024).

soxC-expressing cells were detected at the amputation site beginning at 3–5 hpa, indicating that soxC-expressing cells were supplied and accumulated at the wound site during the first 8 h. Under conditions of soxC RNAi, the number of cells in this region was reduced at 8 hpa, whereas the number of EdU-positive proliferating cells remained unchanged. By 24 hpa, both the total number of cells in this region and the number of proliferating cells had decreased. These results indicated that during the initial 8 hpa, soxC is required for the supply and accumulation of cells in this region rather than for cell proliferation, whereas by 24 h, soxC also contributes to the regulation of cell proliferation (Fujita et al. 2024).

Relationship between soxC-expressing and stem cells

Blastema formation is thought to occur through either the activation of lineage-restricted stem cells or dedifferentiation (Tanaka and Reddien 2011). This poses the question of whether soxC-expressing cells are stem cells. Across diverse animal species, stem cells express GMP genes, which are typically found in germ and pluripotent stem cells across diverse animal species, including piwi, vasa, and nanos (Juliano et al. 2010). For instance, pluripotent stem cells in planarians known as neoblasts express piwi (Reddien et al. 2005), while multipotent stem cells in the Hydra intestine express piwi, vasa, and pl10 (Lim et al. 2014; Plickert, et al. 2012). In acoels, stem cells express GMP genes, including piwi (De Mulder et al. 2009; Gehrke and Srivastava 2016; Srivastava et al. 2014), and acoels are referred to as sister groups to other bilaterians (Cannon et al. 2016; Gehrke et al. 2019; Rouse et al. 2016; Srivastava et al. 2014), suggesting that the expression of GMP genes in stem cells may represent an ancestral feature. In annelids, three regions have been proposed as potential stem cell niches: the posterior growth zone (PGZ) near the tail tip, where new segments are generated; the gonads in segments seven and eight; and putative pluripotent stem cells (named neoblasts by (Randolph 1892)) located ventrally in contact with septa separating body segments Fig. 1d (Ozpolat and Bely 2016). Annelid neoblasts are morphologically and functionally distinct from planarian neoblasts (Myohara 2012). While it has been demonstrated that planarian neoblasts constitute a crucial stem cell population essential for regeneration (Wagner et al. 2011), our current understanding of the specific nature and roles of annelid neoblasts remains very limited (Myohara 2012). Previous studies have partially examined the expression patterns of some GMP genes in E. japonensis (Sugio et al. 2008; 2012; Tadokoro et al. 2006). Fujita et al. (2024) revealed that Ej-vasa1 was expressed in all putative stem cell niches and abundantly in the homeostatic state. These results suggested that Ej-vasa1 can be used as a representative stem cell marker in E. japonensis (Fujita et al. 2024).

The expression of vasa1 during regeneration was investigated. Immediately after amputation, vasa1-expressing cells were observed near the body wall throughout all segments, as observed in the homeostatic state. At 5 hpa, no vasa1-expressing cells were detected at the wound site, whereas soxC-expressing cells were already present. This observation indicated that the two populations are distinct at this stage. At 24 hpa, vasa1-expressing cells appeared in the blastema, although soxC-expressing cells constituted the majority. Partial but not complete overlap of the two populations was further confirmed by double ISH analysis. Collectively, these results indicated that soxC-expressing cells are not necessarily stem cells (Fujita et al. 2024). In annelid regeneration, dedifferentiation is typically defined by the de novo expression of GMP genes (Bely 2014; Kostyuchenko and Kozin 2021; Ozpolat and Bely 2016). Based on this convention, the absence of detectable de novo GMP gene expression prior to the appearance of soxC-expressing cells suggests that dedifferentiation may not be involved, at least with respect to the emergence of soxC-expressing cells.

Conserved feature of soxC-expressing cells in vertebrates and invertebrates

In E. japonensis, soxC-expressing cells play pivotal roles in blastema formation (Fujita et al. 2024). An important question is whether this feature is also observed in other animals. Some vertebrates, such as amphibians, possess a remarkable ability to regenerate lost organs (Stoick-Cooper et al. 2007). Xenopus laevis tadpoles can regenerate their lost tails after amputation and are used as model animals for the study of vertebrate organ regeneration (Beck et al. 2003). The SOXC family is broadly conserved across metazoans, consisting of a single SOXC member in most invertebrates (Heenan et al. 2016), whereas in many vertebrates it comprises three members: SOX4, SOX11, and SOX12 (Angelozzi and Lefebvre 2019). In X. laevis tadpoles, a blastema forms within 48 hpa (Tsujioka et al. 2015). Quantitative RT-PCR analysis of distal tissues containing the blastema at 24 and 48 hpa showed increased expression of Xl-sox4 and Xl-sox11. ISH analysis further revealed that Xl-sox4 expression increased with time around amputation sites at 0, 24, and 48 hpa, while Xl-sox11 expression increased at 0, 6, 24, and 48 hpa. At 48 hpa, both were expressed abundantly in the blastema. These expression dynamics were similar to that for soxC during blastema formation in E. japonensis (Fujita et al. 2024). These findings suggested that SOXC gene(s)-expressing cells are involved in blastema formation not only in invertebrates but also in vertebrates. Given that SOXC genes play a pivotal role in the complex process of blastema formation in invertebrates and vertebrates, it will be important to clarify which signaling pathways involve SOXC gene(s)-expressing cells. In recent years, single-cell RNA (scRNA) sequencing has been applied to X. laevis to gain an understanding of the cellular basis underlying regeneration (Maynard et al. 2024). Using scRNA-sequencing technology, a study discovered regeneration organizing cells (ROCs), localized along the midline edge of the epidermis from the posterior trunk toward the tail tip before amputation. After amputation, they migrated to the amputation site and formed a specialized wound epidermis, and were essential for stimulating tail regrowth (Aztekin et al. 2019). Another study characterized regeneration-initiating cells (RICs), which appeared transiently during the very early phase of regeneration (~ 12 hpa) and were proposed to be formed from basal epidermal cells (Sindelka et al. 2024). Although RICs were referred to as the “laminin-rich epidermis” cluster in the previous study (Aztekin et al. 2019), their regeneration-related properties were further characterized by (Sindelka et al. 2024). At present, the relationship between SOXC gene(s)-expressing cells and ROCs and RICs in X. laevis remains unknown. Interestingly, Xl-sox11 was expressed in RICs (Sindelka et al. 2024). In X. laevis, both SOXC gene(s)-expressing and RIC cells express Xl-sox11 at 6 hpa, suggesting that these cell populations might overlap at least at that time point. Clarifying the relationship between SOXC gene(s)-expressing cells, RICs, and ROCs in X. laevis will be interesting. Further analyses across additional model systems will also be required to clarify the generality of their role in regeneration.

The properties of SOXC gene(s)-expressing cells have been examined in various model systems. SOX4 and SOX11 are highly expressed in embryonic epidermal cells and are re-expressed in postnatal skin wounds in mice (Miao et al. 2019). These factors regulate the expression of downstream cytoskeletal genes required for cell migration. Similarly, during cerebral development in mice, Sox11 inhibition suppresses radial migration of cortical neurons (Hoshiba et al. 2016). Using triple mutant mice, Angelozzi et al. (2022) demonstrated that SOXC genes (SOX4, SOX11, and SOX12) contribute significantly to craniogenesis, likely by controlling the actin cytoskeleton and related activities such as cell proliferation and migration (Angelozzi et al. 2022). In addition, Angelozzi et al. (2024) showed that Sox4 is a critical regulator of adult bone mass(Angelozzi et al. 2024). In zebrafish, knockdown analyses have suggested that sox11b regulates the migration of Müller glia-derived progenitor cells and their fate determination during retinal regeneration (Song et al. 2023). In invertebrates, few studies have examined the association between soxC expression and blastema formation. In the cnidarian polyp Hydra vulgaris, HvSoxC is expressed in a transitional state between i-cells (a type of stem cell) and differentiated cells, suggesting that HvSoxC marks cells undergoing differentiation (Siebert et al. 2019). In mollusks, a marine gastropod, SoxC was suggested to play critical roles in wound repair: fluorescently labeled hemocytes injected into animals migrated to wound sites, where they expressed four Sox genes, including SoxC (Furukawa et al. 2021).SoxC has also been implicated in invertebrate embryogenesis. In the annelid P. dumerilli embryo, Pdu-soxC was expressed in developing central nervous system cells (Kerner et al. 2009). Taken together, these studies suggest that SOXC gene expression may be a common feature of migrating cells or cells in transitional states across diverse biological contexts and animal species.

Are the soxC-expressing cells blastema precursor cells?

Expression analysis during blastema formation in E. japonensis showed that soxC-expressing cells were not detected immediately after amputation but appeared subsequently near the body wall and seemed to gradually accumulate in the blastema. Furthermore, cell proliferation analysis suggested that soxC-expressing cells were supplied from elsewhere and accumulated at the wound site for up to 8 hpa. RNAi experiments further demonstrated that soxC is required for blastema formation (Fujita et al. 2024). Considering these characteristics, we hypothesized that soxC-expressing cells may represent "blastema precursor cells" that migrate to the wound site Fig. 2a. Future lineage-tracing experiments will shed more light on this possibility.

Future perspectives

In this review, we primarily introduced an annelid model system for regenerative biology and discussed the importance of soxC-expressing cells during blastema formation. A key challenge for future research is to determine whether soxC-expressing cells arise through the activation of resident stem cells (e.g., vasa1-expressing cells) or through dedifferentiation. In recent years, successful examples of scRNA-seq analyses focusing on regeneration in annelids have begun to emerge (Alvarez-Campos et al. 2024; Shao et al. 2020; Stockinger et al. 2024). Employing single-cell resolution analysis to decipher the cellular features of soxC-expressing cells, which exhibit characteristic expression dynamics during blastema formation is also crucial for blastema research in E. japonensis. While research tools for annelid studies are still limited, P. dumerilii research utilizing transgenic animals for lineage tracing has been achieved (Backfisch et al. 2014; 2013; Stockinger et al. 2024). The development of such lineage-tracing tools is also desirable for the E. japonensis research system. Furthermore, SOXC gene(s)-expressing cells in X. laevis tadpoles were implicated to have conserved roles similar to those of soxC during blastema formation in E. japonensis. By clarifying the relationship between SOXC gene(s)-expressing cells, RICs, and ROCs in X. laevis, we can gain insights into the extent to which the association between blastema formation and SOXC gene(s)-expressing cells is conserved across animal species. Clarifying the relationship between soxC and Wnt signaling during blastema formation may reveal whether a conserved SoxC–Wnt interaction operates during regeneration. For example, SoxC proteins have been shown to amplify canonical Wnt signaling by stabilizing β-catenin during mouse skeletogenesis (Bhattaram et al. 2014). To further advance our understanding of blastema formation, we should investigate how soxC gene(s)-expressing cells contribute to this process, including their role in key signaling pathways Fig. 2c.

Acknowledgements

We thank the anonymous reviewers for their constructive comments and suggestions, which greatly helped us improve our manuscript. We also thank Editage (www.editage.com) for English language editing.

Author contributions

TF and SY conceived and wrote the review together, and approved the submitted version.

Funding

This study was supported by a Teikyo University Research Encouragement Grant (T.F.), ACRO Team Research Grants of Teikyo University (T.F., S.Y.), ACRO incubation Grant of Teikyo University (T.F., S.Y.), The research foundation for Pharmaceutical Sciences (RFPS) (T.F.), a Fund for the Promotion of Joint International Research (Fostering Joint International Research [B]) (T. F.), Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (S.Y., 25K09943, 21K06535, 18K06667, 15K07945).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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