You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic. For video creation, please contact our Academic Video Service.
Version Summary Created by Modification Content Size Created at Operation
1 Rong Mou -- 4012 2022-12-29 10:37:54 |
2 format Jason Zhu Meta information modification 4012 2022-12-30 02:46:33 |

Video Upload Options

We provide professional Academic Video Service to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Mou, R.;  Chen, K.;  Zhu, P.;  Xu, Q.;  Ma, L. Stem/Progenitor Cells on Lymphangiogenesis in Vascular Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/39575 (accessed on 08 December 2025).
Mou R,  Chen K,  Zhu P,  Xu Q,  Ma L. Stem/Progenitor Cells on Lymphangiogenesis in Vascular Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/39575. Accessed December 08, 2025.
Mou, Rong, Kai Chen, Pengwei Zhu, Qingbo Xu, Liang Ma. "Stem/Progenitor Cells on Lymphangiogenesis in Vascular Disease" Encyclopedia, https://encyclopedia.pub/entry/39575 (accessed December 08, 2025).
Mou, R.,  Chen, K.,  Zhu, P.,  Xu, Q., & Ma, L. (2022, December 29). Stem/Progenitor Cells on Lymphangiogenesis in Vascular Disease. In Encyclopedia. https://encyclopedia.pub/entry/39575
Mou, Rong, et al. "Stem/Progenitor Cells on Lymphangiogenesis in Vascular Disease." Encyclopedia. Web. 29 December, 2022.
Stem/Progenitor Cells on Lymphangiogenesis in Vascular Disease
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cells11244056

Lymphatic vessels, as the main tube network of fluid drainage and leukocyte transfer, are responsible for the maintenance of homeostasis and pathological repairment. By using genetic lineage tracing and single-cell RNA sequencing techniques, significant cognitive progress has been made about the impact of stem/progenitor cells during lymphangiogenesis. In the embryonic stage, the lymphatic network is primarily formed through self-proliferation and polarized-sprouting from the lymph sacs. However, the assembly of lymphatic stem/progenitor cells also guarantees the sustained growth of lymphvasculogenesis to obtain the entire function. In addition, there are abundant sources of stem/progenitor cells in postnatal tissues, including circulating progenitors, mesenchymal stem cells, and adipose tissue stem cells, which can directly differentiate into lymphatic endothelial cells and participate in lymphangiogenesis. 

stem cells progenitors lymphangiogenesis lymphavasculogenesis

1. Introduction

The lymphatic vasculature, a complicated blind-ended structure, is responsible for draining the extra interstitial liquid back to the blood circulation, mediating lymphocyte activation, and participating in immune responses [1]. Although most organs/tissues contain lymphatics, so far, no conventional lymphatic vasculature has been identified within the brain (with the exception of meninges) [2][3], bone marrow [4], the posterior part of the eye (retina/choroid/lens/vitreous body) [5][6], and the renal medulla [7][8]. Since the recycling fluid absorbed by lymphatic vessels is ultimately collected into the venous system, the lymphatic vessel system is also considered an important complement to the venous system. Except for the conventional regulation mentioned above, the lymphatic system also takes charge of lipid absorption, immune control, and reverse cholesterol transportation. Importantly, defects in lymphatic function can result in tissue edema and impaired immune responses. With increasing evidence declaring that lymphangiogenesis is closely associated with the prognosis of tissue injury, tumor metastasis, and organ transplantation, it gradually attracted the broad attention of researchers.
Ever since Sabin [9] first proposed that the lymphatic vasculature was derived from veins using an embryo ink injection experiment, an intense debate about the existence of stem/progenitor cells in lymphangiogenesis has continued for over a hundred years. Until recently, the origins of lymphangiogenesis could be concluded into three ways, including originating from the cardinal vein, differentiating from lymphatic stem/progenitor cells, and transdifferentiating from existing blood vessels. Except for the classical venous-derived generation, cells that possess potential differentiation capability, such as hematopoietic cells [10], lymphatic endothelial progenitor cells [11][12], mesenchymal stem cells [13], myeloid lineage cells [14], and adipose-derived stem cells [15], are underestimated. These cells not only appear during the embryonic stage, but also play a significant role in the postnatal lymphangiogenesis in response to various stimuli. For this reason, the exploration of the application of lymphatic stem/progenitor cells to affect the disease process becomes instructive.

2. Progenitor Cells in Embryonic Lymphatic Vasculature Generation

The formation of embryonic lymphvasculogenesis theory could date back to 1902, when Sabin first observed the primitive lymph sacs bud from the pre-existing veins, which initially brings the opinion that venous endothelium was an indispensable source for lymphatic endothelium [9]. However, early descriptive studies by Huntington and McClure [16] suggested that the lymphatic vascular system could develop from mesenchymal lymphangioblasts without any contribution from embryonic veins, which was the first opposing viewpoint. Thereout, whether the lymphatic progenitor cells exist throughout a prenatal organism lifetime soon raised lengthy controversial discussions. Interestingly, in the 2010s there appeared numerous studies that validated Sabin’s vein-derived hypothesis and insisted a solely venous-derived mammalian lymphatic system [17]. But at the same time, people began to realize that there was a huge distinction between embryonic lymphatic origins across species. A collection of studies, which widely involved different species, from the non-mammalian such as birds [18], Xenopus [19], and zebrafish [20][21], to the mammalian-like mouse [17][22][23][24][25], successfully substantiated the dual origins of lymphvasculogenesis in embryos. Admittedly, previous experiments largely relied on skilled and meticulous observation. However, in the last decade, attributed to multiple advanced techniques, including high-resolution microscopy, genetic cell lineage tracing, and single-cell RNA sequencing, more solid data have been obtained and have directly replenished the evidence about the involvement of stem/progenitor cells in lymphatic vasculature generation.

2.1. Embryonic Lymphangiogenesis (Physiological Process)

After many years of research, it has been concluded that nearly all embryonic mammalian lymphatic endothelial cells (LECs) are venous-derived, while some organs and tissues possess diverse non-venous-derived sources in the later embryonic period. Specifically, later than the formation of the vascular system, which is established at around embryo day (E) 9.5, the first lymphatic progenitor cells, Prox1-positive cells, emerge as a polarized cell population within the dorso-lateral aspect of the cardinal and intersomatic veins [25][26]. Importantly, these Prox1-expressing cells are viewed as crucial regulators to specify LEC fate. Compared with previous bipotent endothelial cells in veins, the expression of mature vein endothelial markers, such as CD34 and vWVF, is downregulated in Prox1-expressing cells [27]. Nearly at the same time, LYVE1 is expressed in the venous-derived lymphatic endothelium, which represents the first symbol of the beginning of lymphvasculogenesis. Through a step-wise process, these lymphatic progenitor cells bud and balloon from veins and then migrate and reorganize into lumenal structures to construct the primary lymph sacs [25][26][28]. The formation of primitive lymph sacs is considered as an initial step to the anatomical change in lymphvasculogenesis. Interestingly, Oliver [27] summarized a working model of lymphatic vasculature development and pinpointed that the increased expression of LEC markers would in turn irreversibly propel cell fate toward the lymphatic pathway. Furthermore, endothelial markers are different from organs and tissues, and a review of organ-specific lymphatic vasculature was published as a good reference to acknowledge [29]. Upon terminal differentiation, mature LECs permanently expressed specific cell-type characteristic markers including LYVE-1, Prox-1, and Podoplanin [30]. Prox1 is a transcription factor that is involved in various developmental processes such as cell-fate determination and progenitor cell regulation in a number of organs, plays a critical role in embryonic development, and functions as a key regulatory protein in lymphangiogenesis. Podoplanin is a transmembrane glycoprotein that plays a role in blood and lymphatic vessels separation by triggering C-type lectin domain family 1 member B activation in platelets, leading to platelet activation and aggregation [31][32][33][34][35]. By binding with lactose agglutinin 8, Podoplanin may also participate in the connection of the lymphatic endothelium to the surrounding extracellular matrix. LYVE1 is identified as a major receptor for extracellular matrix glycosaminoglycan hyaluronan on the lymph vessel wall. LYVE1 plays a role in transporting hyaluronan into lymphatic endothelial cells for catabolism and into the lumen of afferent lymphatic vessels reversely as well [36]. It facilitates leukocyte adhesion and migration through lymphatic endothelium by binds to pericelluar hyaluronan matrices [37]. VEGFR3 is a tyrosine kinase receptor for vascular endothelial growth factors VEGF-C and D, which appear to play a role in lymphangiogenesis and the maintenance of the lymphatic endothelium.
There was a previous hypothesis indicating that lymph sacs ultimately transform into lymph nodes, which was refuted by Vondenhoff et al. [38], who believed that the initiation of mammalian lymph node formation and the accumulation of initial clusters of lymphoid-tissue-inducer cells did not require lymph sacs. This swarming behaviour of lymphoid-tissue-inducer cells is considered as a vital step to form ordered lymphoid structure as well as a consequence of a self-organizing system [39]. After egress from the cardinal vein, the shape of those Prox1+ cells changed from round to oblong until E10.5. At around E12.5, lymphoid-tissue-inducer cells initially cluster to start lymph-node formation [40], which seems to be independent action due to the absence of lymphatic vessels formation nearby. After the initial organization of this process, lymphoid-tissue-inducer cells could be further attracted by CCL21 expressed by LECs [40]. Following the first interactions of lymphoid-tissue-inducer cells with lymphoid-tissue-organizer cells, the induction of VEGF-C expression by lymphoid-tissue-organizer cells is induced and subsequently mediates LECs approach to the lymphatic sacs [41]. The lymphatic node will be completely formed on the seventh day after birth. Moreover, there is a rapid accumulation of Prox1+ cells, which extend dorsally to form the peripheral longitudinal lymphatic vessel and further a continuous structure, superficial LECs. Simultaneously, another larger luminal structure, which is closer to the cardinal vein, the primordial thoracic duct, gradually appears. It is connected via a bow-shaped structure with the peripheral longitudinal lymphatic vessel towards its cranial end and develops anatomically in a position corresponding to that of the mature thoracic duct [42]. Finally, the lymphatic network is formed through self-proliferation and polarized-sprouting from the lymph sacs and undergoes sustained growth, remodeling, and maturation to obtain the entire function. Lymph flows into the collecting lymphatic vessels after gathering in the lymphatic capillaries. The collecting lymphatic vessels of the entire body finally converge into two big trunks, that is, the thoracic duct and the right lymphatic duct. The lymph finally enters the blood circulation at the junction of the subclavian veins and the internal jugular veins on both sides.

2.2. Venous-Derived Lymphatic Progenitor Cells

Around E9.5, endothelial cells in the dorsal wall of the cardinal vein are the earliest source of Prox1-expressing LEC progenitors [17][25][26]. Prox1-expressing cells, the regulators to determine LEC destiny, separate themselves from the cardinal vein and then bud into stroma in response to VEGF-C/VEGFR3 signaling. While most Prox1-expressing lymphatic progenitor cells will eventually vacate the veins, there are still a few of them that stay and become part of the lymphovenous valves [23]. Acknowledging the cornerstone role of the Prox1+ subpopulation of endothelial cells in lymphatic vasculogenesis [25], researchers naturally found a deficiency of Prox1 expression in LEC progenitors among venous endothelial cells in the anterior cardinal veins. Expectedly, the budding and sprouting of the lymphatic system was vanished in Prox1 null mice but the vascular system remained unaffected. So many investigators tend to use the conditional knockout of Prox1 using CreER/CreERT2 mice to discuss the relationship between the LEC progenitor and specific source [10][43].
Utilizing different lineage-tracing animals is the basic strategy to validate the hypothesis of venous origin. For instance, a receptor tyrosine kinase expressed in blood endothelial cells and hematopoietic cells, Tie2, is the most adopt marker to trace the venous origin. Cardiac lymphatics have been reported to appear at E12.5, shortly after the development of the coronary vasculature, and integrally formed the complete lymphatic network by P15 [10][44]. Scientists used venous specific Tie2-CreER, Apj-CreER, endothelial-specific Cre lines Sox18-CreERT2, and Cdh5-CreERT2 mice to prove that the majority of cardiac lymphatics were derived from veins [45][46][47]. However, there were still a few lymphatic vessels that were not labeled, in consideration of the high recombination rate of these two drivers, and it implied that the possibility of non-venous origin remained existing. As a solution, Pdgfrb-Cre for labeling mural cells, including the vascular smooth muscle cells, pericytes, and hepatic stellate cells, was used and succeeded in tracking embryo LECs in the heart and found evidence about the non-venous-derived origins [10][48]. To summarize, while the non-venous origins show the heterogeneity of lymphatic progenitor cells, the venous-derived origin is still predominant in multiple organs.

2.3. Non-Venous-Derived Lymphatic Progenitor Cells

Among the lineage-tracing strategies of mouse embryos, Runx1-expressing cells, labeling the hematopoietic components, are shown to not be involved in the lymph sacs formation or lymphatic vasculature [17]. Similarly, by using Kit-CreERT2 and Gata2-deficient embryos, Pichol-Thievend et al. [47] excluded the hematogenic endothelium as a source of LEC progenitors in embryonic mouse skin. However, while Martinez-Corral et al. [22] found the comparable performance in dermal LECs through tracing Tie2-positive endothelial/hematopoietic cells and Vav-definitive hematopoietic cells, they surprisingly found that part of the mesenteric lymphatic vasculature was from c-Kit lineage progenitor cells, which were conventionally regarded as the hemogenic endothelial origin [48]. It was worth noting that the dual origin of mesenteric lymphatic vessels was declared by Mahadevan et al., that there exists a separate population of lymphatic progenitors that forms mesenteric lymphatic vasculature, which is dependent on the expression of Pitx2 (paired-liked homodomain transcription factor-2) [49]. These findings provided solid evidence, indicating that the differentiation potential of non-venous-derived lymphatic progenitor cells is not homogenous in different organs or tissues. In other words, the therapeutic use for lymphatic vasculature regeneration should characterize in consideration of the corresponding cellular sources of progenitors, which may not be useful. Analogously, the lymphatic vasculature of embryonic mouse heart was proven to be derived from both extra-cardiac venous endothelium and lymphatic endothelial progenitors in yolk sac haemogenic endothelium [10]. The initial negative results about hematopoietic cells may be explained by the oversight of organ specificity and an incomplete yolk sac, including aggregations and primitive hematopoietic derivatives labeling. More precisely, Klotz et al. [10] confirmed the contribution of the yolk sac by Vav1-Cre; R26-tdTomato mice, therefore, ensured Vav1 hemogenic lineage contributed to cardiac LECs as a non-venous origin. However, the contribution of hematopoietic cells integrating into lymphatic vasculature is very small and the dysplasia of cardiac lymphatic vessels during the Tie2-Cre; Prox1fl/fl mutants’ embryo period, is recoverable after birth.
Moreover, using Csf1r-iCre; Z/EG (lacZ/EGFP) and LysMCre; ROSA26R mice to label myeloid lineage cells, Gordon, E.J., et al. [50] excluded macrophages as a reservoir of lymphatic endothelial progenitor cells in both the mouse embryo and the tumor microenvironment. Though they detected myeloid LYVE1+ macrophages and seemed to locally integrate into lymphatic vessels, the absence of a crucial marker of lymphatic endothelial cell identity PROX1 explained that they are just undergoing the intimate association but not the identity transformation [10]. The above evidence additionally emphasized that the detection of important LEC markers was necessary to distinguish the facticity of transdifferentiation. Hence, the previous statement about lymphatic endothelial progenitors in yolk sac haemogenic endothelia is being queried. Lineage-tracing analysis in transplantation studies revealed that PAX3+ [51] (arising embryonic myoblasts and myofibers), VEGFR2+ (highlighting hematopoietic, vascular, and muscle cells) [52], and Myf5+ (initiating muscle differentiation) somitic cells [53] are able to differentiate into endothelial cells as bipotent precursors for the skeletal muscle and endothelium of the limb, while the source of Prox1+ lymphatic progenitors and endothelial cells in the dorso-lateral wall of the E9.5 cardinal vein is considered to be derived from the Pax3 lineage [53]. Additionally, the second heart field, a multipotent cell population managing heart morphogenesis, labeled by Isl1-expressing progenitors in the pharyngeal region, also serves as a source of LECs [43]. In conclusion, improved lineage-tracing techniques and rigor definition for LEC differentiation are conducive to the recognition of non-venous-derived lymphatic progenitor cells.

3. Stem/Progenitor Cells in Postnatal Lymphangiogenesis

Under physiological conditions, lymphangiogenesis does not only exist in the embryo stage, but also happens in the postnatal period. To illustrate, Schlemm’s canal, lined by endothelial cells expressing LEC markers (PROX1, VEGFR3, integrin α9) [54][55][56][57], is a lymphatic intermediate vessel with the function of draining aqueous humor [29]. The Schlemm’s canal is originated from transscleral veins that are derived from episcleral and choroidal vessel plexus [54][58] and acquired lymphatic phenotypes through upregulating PROX1 [56]. Subsequently, Tie2 is expressed in the PROX1+ Schlemm’s canal endothelial cells and maintained at a high level to critically regulate integrity during adulthood [59]. VEGF-C/VEGFR3 signaling also plays a crucial role in the development of Schlemm’s canal, delivering VEGF-C into adult eyes leading to the sprouting, proliferation, and growth of Schlemm’s canal [54]. For another example, intestinal lacteal, a lymphatic capillary in the intestinal villi, plays an important role in absorbing nutrients and tracking immune cells into mesenteric lymph nodes [60]. Contrasted with the majority of adults lymphatic vessels, which are quiescent, the intestinal lacteals show permanent regeneration under physiological conditions [61][62]. In 2015, Bernier-Latmani et al. demonstrated that the activation of VEGFR3 and VEGFR2 leads to the expression of DLL4 and thus activates the NOTCH signaling, inducing the proliferation of intestinal lacteal [61].
In contrast to the physiological process of lymphangiogenesis after birth, it seems that people are keen to pay attention to pathological conditions. As evidenced in chronic inflammation [63], acute injury [64], tumorigenesis [65][66], and organ transplantation [67], the presence of lymphangiogenesis is considered as a critical event mediating liquid drainage and immune reactions during the postnatal period. Instead of sprouting, remodeling, and maturation from pre-existing lymphatic vessels, lymphangiogensis is also dependent on the contribution of stem/progenitor cells.

3.1. Lymphatic Endothelial Progenitor Cells

Lymphatic endothelial progenitor cells (LEPCs) have been recognized as main contributors to developmental and postnatal lymphangiogenesis [11][12]. The broad participations of LEPCs are declared in injury, inflammation, tumor, and transplantation [68][69]. As an important source of LEPCs, the isolation of peripheral blood cells can successfully acquire two distinguishable circulating progenitors, including classical endothelial progenitors (high-level expression of VEGFR-1 but low-level VEGFR-3) and LEPCs (high-level expression of PROX-1, VEGFR-3, Podoplanin, and LYVE-1 but low-level VEGFR-1) [70]. In addition, the existence of an analogous group (VEGFR3+/Podoplanin+/CD11b+ LEPCs) has also been confirmed in human umbilical cord blood [71].
For the application, the impairment of lymphatic drainage generally occurs in cardiovascular diseases and is commonly viewed as an aggravating factor to exacerbate cardiac edema, inflammation, fibrosis, and arrhythmia [72][73]. Since CD34+VEGFR3+PROX1+CD45−CD11b−CD68− LEPCs isolated from bone marrow have been reported to possess a great potential to differentiate towards LECs, injecting or transplanting LEPCs to stimulate lymphangiogenesis becomes a potent therapeutic method [74]. In fact, CD34+ VEGFR3+ LEPCs isolated from bone marrow were injected into myocardium around the peri-infarct region and consequently transdifferentiated and incorporated into lymphatic vessels, which did not contribute to blood endothelial cells [74]. Admittedly, the LEPC-induced repair process does not always act as a rapid response, so the improvements to promote the survival, retention, and viability of transplanted LEPCs remain a challenge for future therapeutic approaches. Interestingly, a subpopulation in human fetale, labeled with CD34 and VEGFR3 cells, co-expresses the stem cell marker CD133, suggesting the other existence of lymphatic progenitor cells in the human body [75].

3.2. Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are a subpopulation of stem cells, which are usually isolated from the umbilical cord, bone marrow, and adipose tissue. MSCs are known for their great potential to differentiate into bone, fat, and endothelial cells within multiple tissues [76]. Moreover, MSCs were also sensitive to the lymphangiogenic VEGF-C signal and were inclined to acquire a lymphatic phenotype both in vivo and in vitro [77]. For instance, the TGF-β-responsive, VEGFR-3-positive SG-2 MSCs, which retain both osteogenic and adipogenic differentiation potentials, can be induced to differentiate into LECs by VEGF-C stimulation or inhibited by TGF-β signal [13]. In the wounded heart suffering from myocardial infarction, a group of mesenchymal markers, PDGFRα+ MSCs with concurrent high expressions of podopanin, Prox-1, and VEGFR-3, manifest a predominant ability to generate lymphatic endothelial cells and impact the outcome of the myocardial repair process [69]. In addition, autologous stem cell therapy usually adopts mesenchymal stem cells as a reliable and suitable source to treat limb ischemia [78]. However, the difficulty and costliness to get sufficient stem cell storage limits the diffusion of application. Herein, people turn to utilize the xenograft of porcine MSCs. Yamada et al. [79] proposed that xenotransplantation of porcine bone marrow MSCs contributed to the improvement of mouse hind limb ischemia through both angiogenesis and especially lymphangiogenesis, showing the potential of being an alternative source for stem cell therapy.
Despite increasing lymphangiogenesis being beneficial in lymphedema after injury, the swelling due to lymph accumulation in the extracellular space, it does not always acquire same compliment especially when involved with tumor prognosis and organ transplantations. In other words, lymphangiogenesis can be a double-edged sword, which can be evidently embodied in the application of MSCs. The hypoxia microenvironment caused by tumorigenesis or transplantation surgeries tends to attract and stimulate the MSCs accumulation. On this aspect, the following proliferation of lymphangiogenesis by MSC differentiation and the remodeling of existing lymphatics are thought to be the initial events in cancer metastasis and inducing immunological rejection. These consequences make the generation of lymphatics a harmful biological behavior [65][66]. Hence, it can be predicted that the suppressing of the VEGF-C/VEGFR3 pathway will decrease the lymphatic fluid drainage in cardiac and cornea allografts, reduce the negative effect of both innate and adaptive immunity, and therefore prolonged the survival time of grafted organs [80][81]. In this situation, the specific-disease-associated mechanisms have warned MSCs induced the generation of lymphangiogenesis, and the therapy should be carefully discussed.

3.3. Myeloid Lineage Cells

Myeloid lineage cells have been established to play important roles during both embryonic- and inflammation-stimulated lymphangiogenesis [50][82][83]. Previously, Maruyama et al. [14] reported that macrophages could support the lymphangiogenesis either by transdifferentiation or stimulating preexisting lymphatics, regarding macrophages as a source of VEGF-C to trigger the growth or hyperplasia of lymphatic vessels. Maruyama et al. [14] mentioned that myeloid cells contributed to lymphangiogenesis in the inflamed cornea and had the ability to form lymphatic vessel-like structures in vitro. In fact, different macrophage subtypes have been well defined by specific markers and corresponding lineage-tracing techniques. Among various subtypes, M1/M2 type macrophages were distinguished by the promotive or suppressive effect on the inflammatory responses, and this discrepancy also influences their impact on the lymphangiogenesis [84][85][86][87]. Specifically, in the renal fibrosis microenvironment, M1 macrophages were deemed as stimulative factors and could contribute to the lymphangiogenesis through the classical VEGF-C/VEGFR3 signaling pathway. Furthermore, by promoting M1-macrophage polarization and increasing the LEC expression, M1 macrophages could transdifferentiate into LECs both in vivo and in vitro [88]. Comparatively speaking, M2 macrophages, characterized by eliminating inflammation to promote tissue repairment [89], were considered to have a low inclination to transdifferentiate into LECs, as proved by the low expression of lymphatic endothelium markers [90]. To trace the fate of cells of the myeloid lineage during tumor lymphangiogenesis, Zumsteg et al. [82] transplanted TRAMP-C1 murine prostate cancer cells into CD11b-Cre; Z/EG mice and subsequently detected the LYVE-1, Prox-1, and F4/80 triple-positive cells in tumor lymphatic vessels, testifying an already myeloid-committed hematopoietic lineage origin. In another tumor implantation model, Podoplanin+CD11b+ cells derived from bone marrow can function as lymphatic progenitor cells and participate in postnatal lymphatic neovascularization through both lymphvasculogenesis and lymphangiogenesis [91]. Whereas, the opposing evidence showed that in adult LysMCre; ROSA26R mice implanted with Lewis lung carcinoma or EL4 lymphoma cells, lymphangiogenesis arose independently of the macrophage lineage, a phenomenon similarly reported in tumor-stimulated lymphangiogenesis [50]. Except for macrophages, monocytes in vitro might also transdifferentiate into either blood vascular endothelial cells or lymphatic endothelial cells, and the LEC phenotype is easier to acquire under an inflammatory environment [92][93][94]. CD14+ monocytes induced by the endothelial medium EGM2 are able to express lymphatic endothelial markers Prox-1, VEGFR-3, LYVE-1, Podoplanin, and pan-endothelial markers vWF, CD144, and VEGFR-2 [95], but it has not been confirmed by in vivo models.

3.4. Adipose-Tissue-Derived Stem Cells

Lymphedema is a chronic disease, which ultimately causes severe and permanent damage within involved organs. Among the underlying stem cell treatments, adipose-tissue-derived stem cells’ (ADSCs) extraction is known for minimal donor site impairment and less discomfort from patients. Except for the non-invasive harvesting technique, ADSCs also possess other advantages, such as convenient acquisition because they are easily isolated from adipose sediment after digestion, higher proliferative capacity, and stronger genetic and morphologic stability. Therefore, ADSCs are constantly regarded as potential therapeutic targets in various diseases, especially in lymphedema.
In vitro ADSCs are usually defined as positive for CD13, CD29, CD44, CD49d, CD73, CD90, and CD105 and negative for hematopoietic cell markers such as CD14, CD31, CD45, and CD144 [15]. By being injecting with ADSCs, both animals and human generally therefore benefited from lymphedema treatment, showing that ADSC-based therapy is an important key to the future treatment for secondary lymphedema [96][97]. However, the view of this differentiation was only verified in vitro, and it seems more promising to figure out how the paracrine action occurs.
Apart from the direct differentiation ability, the paracrine effect of ADSCs has been elucidated. Compared with the bone-marrow-derived MSCs, ADSCs display more immunomodulatory functions with secreting basic fibroblast growth factor, interferon-γ, insulin-like growth factor-1, VEGF-C, and HGF [98][99]. More importantly, the secreting components would constantly adapt to the changing microenvironment, and this characteristic perfectly fits the continuously changed homeostasis of tumor, ischemia, and tissue injury. For example, in hypoxia, ADSC-derived extracellular vesicles are loaded with decreased exosomal miR-129 expression, which resulted in the upregulation of HMGB1 in LECs and led to AKT activation and lymphangiogenesis enhancement [100]. Another aspect of injection, in addition to exosome secretion, adipose-tissue-derived microvascular fragments, carrying segments of micro blood/lymphatic vessels as well as other stem cells such as endothelial progenitor cells (Sca-1+/VEGFR-2+) and multipotent mesenchymal stromal cells (CD29+, CD44+, CD73+, CD90+, and CD117+), have attracted much attention [101]. Although this therapeutic method has not been extensively used, it can really help to differentiate LECs by utilizing the current existing stem cells, but is still waiting for further verification.

References

  1. Schulte-Merker, S.; Sabine, A.; Petrova, T.V. Lymphatic vascular morphogenesis in development, physiology, and disease. J. Cell Biol. 2011, 193, 607–618.
  2. Sun, B.L.; Wang, L.H.; Yang, T.; Sun, J.Y.; Mao, L.L.; Yang, M.F.; Yuan, H.; Colvin, R.A.; Yang, X.Y. Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases. Prog. Neurobiol. 2018, 163–164, 118–143.
  3. Raper, D.; Louveau, A.; Kipnis, J. How Do Meningeal Lymphatic Vessels Drain the CNS? Trends Neurosci. 2016, 39, 581–586.
  4. Oliver, G.; Kipnis, J.; Randolph, G.J.; Harvey, N.L. The Lymphatic Vasculature in the 21(st) Century: Novel Functional Roles in Homeostasis and Disease. Cell 2020, 182, 270–296.
  5. Schroedl, F.; Kaser-Eichberger, A.; Schlereth, S.L.; Bock, F.; Regenfuss, B.; Reitsamer, H.A.; Lutty, G.A.; Maruyama, K.; Chen, L.; Lutjen-Drecoll, E.; et al. Consensus statement on the immunohistochemical detection of ocular lymphatic vessels. Investig. Ophthalmol. Vis. Sci. 2014, 55, 6440–6442.
  6. Koina, M.E.; Baxter, L.; Adamson, S.J.; Arfuso, F.; Hu, P.; Madigan, M.C.; Chan-Ling, T. Evidence for lymphatics in the developing and adult human choroid. Investig. Ophthalmol. Vis. Sci. 2015, 56, 1310–1327.
  7. Kenig-Kozlovsky, Y.; Scott, R.P.; Onay, T.; Carota, I.A.; Thomson, B.R.; Gil, H.J.; Ramirez, V.; Yamaguchi, S.; Tanna, C.E.; Heinen, S.; et al. Ascending Vasa Recta Are Angiopoietin/Tie2-Dependent Lymphatic-Like Vessels. J. Am. Soc. Nephrol. 2018, 29, 1097–1107.
  8. McIntosh, G.H.; Morris, B. The lymphatics of the kidney and the formation of renal lymph. J. Physiol. 1971, 214, 365–376.
  9. Sabin, F.R. On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. Am. J. Anat. 1902, 1, 367–389.
  10. Klotz, L.; Norman, S.; Vieira, J.M.; Masters, M.; Rohling, M.; Dube, K.N.; Bollini, S.; Matsuzaki, F.; Carr, C.A.; Riley, P.R. Cardiac lymphatics are heterogeneous in origin and respond to injury. Nature 2015, 522, 62–67.
  11. Park, C.; Lee, J.Y.; Yoon, Y.S. Role of bone marrow-derived lymphatic endothelial progenitor cells for lymphatic neovascularization. Trends Cardiovasc. Med. 2011, 21, 135–140.
  12. Kazenwadel, J.; Harvey, N.L. Lymphatic endothelial progenitor cells: Origins and roles in lymphangiogenesis. Curr. Opin. Immunol. 2018, 53, 81–87.
  13. Igarashi, Y.; Chosa, N.; Sawada, S.; Kondo, H.; Yaegashi, T.; Ishisaki, A. VEGF-C and TGF-beta reciprocally regulate mesenchymal stem cell commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes. Int. J. Mol. Med. 2016, 37, 1005–1013.
  14. Maruyama, K.; Ii, M.; Cursiefen, C.; Jackson, D.G.; Keino, H.; Tomita, M.; Van Rooijen, N.; Takenaka, H.; D’Amore, P.A.; Stein-Streilein, J.; et al. Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J. Clin. Investig. 2005, 115, 2363–2372.
  15. Ahmadzadeh, N.; Robering, J.W.; Kengelbach-Weigand, A.; Al-Abboodi, M.; Beier, J.P.; Horch, R.E.; Boos, A.M. Human adipose-derived stem cells support lymphangiogenesis in vitro by secretion of lymphangiogenic factors. Exp. Cell Res. 2020, 388, 111816.
  16. Huntington, G.S.; McClure, C.F.W. Symposium on the development and structure of the lymphatic system. I. The anatomy and development of the jugular lymph sacs in the domestic cat (Felis dornestica). Anat. Rec. 1908, 2, 1–18.
  17. Srinivasan, R.S.; Dillard, M.E.; Lagutin, O.V.; Lin, F.J.; Tsai, S.; Tsai, M.J.; Samokhvalov, I.M.; Oliver, G. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. 2007, 21, 2422–2432.
  18. Wilting, J.; Aref, Y.; Huang, R.; Tomarev, S.I.; Schweigerer, L.; Christ, B.; Valasek, P.; Papoutsi, M. Dual origin of avian lymphatics. Dev. Biol. 2006, 292, 165–173.
  19. Ny, A.; Koch, M.; Schneider, M.; Neven, E.; Tong, R.T.; Maity, S.; Fischer, C.; Plaisance, S.; Lambrechts, D.; Heligon, C.; et al. A genetic Xenopus laevis tadpole model to study lymphangiogenesis. Nat. Med. 2005, 11, 998–1004.
  20. Eng, T.C.; Chen, W.; Okuda, K.S.; Misa, J.P.; Padberg, Y.; Crosier, K.E.; Crosier, P.S.; Hall, C.J.; Schulte-Merker, S.; Hogan, B.M.; et al. Zebrafish facial lymphatics develop through sequential addition of venous and non-venous progenitors. EMBO Rep. 2019, 20, e47079.
  21. Yaniv, K.; Isogai, S.; Castranova, D.; Dye, L.; Hitomi, J.; Weinstein, B.M. Live imaging of lymphatic development in the zebrafish. Nat. Med. 2006, 12, 711–716.
  22. Martinez-Corral, I.; Ulvmar, M.H.; Stanczuk, L.; Tatin, F.; Kizhatil, K.; John, S.W.; Alitalo, K.; Ortega, S.; Makinen, T. Nonvenous origin of dermal lymphatic vasculature. Circ. Res. 2015, 116, 1649–1654.
  23. Yang, Y.; Garcia-Verdugo, J.M.; Soriano-Navarro, M.; Srinivasan, R.S.; Scallan, J.P.; Singh, M.K.; Epstein, J.A.; Oliver, G. Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos. Blood 2012, 120, 2340–2348.
  24. Kaipainen, A.; Korhonen, J.; Mustonen, T.; van Hinsbergh, V.W.; Fang, G.H.; Dumont, D.; Breitman, M.; Alitalo, K. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc. Natl. Acad. Sci. USA 1995, 92, 3566–3570.
  25. Wigle, J.T.; Oliver, G. Prox1 function is required for the development of the murine lymphatic system. Cell 1999, 98, 769–778.
  26. Francois, M.; Short, K.; Secker, G.A.; Combes, A.; Schwarz, Q.; Davidson, T.L.; Smyth, I.; Hong, Y.K.; Harvey, N.L.; Koopman, P. Segmental territories along the cardinal veins generate lymph sacs via a ballooning mechanism during embryonic lymphangiogenesis in mice. Dev. Biol. 2012, 364, 89–98.
  27. Oliver, G. Lymphatic endothelial cell fate specification in the mammalian embryo: An historical perspective. Dev. Biol. 2022, 482, 44–54.
  28. Wigle, J.T.; Harvey, N.; Detmar, M.; Lagutina, I.; Grosveld, G.; Gunn, M.D.; Jackson, D.G.; Oliver, G. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 2002, 21, 1505–1513.
  29. Petrova, T.V.; Koh, G.Y. Organ-specific lymphatic vasculature: From development to pathophysiology. J. Exp. Med. 2018, 215, 35–49.
  30. Bronneke, S.; Bruckner, B.; Peters, N.; Bosch, T.C.; Stab, F.; Wenck, H.; Hagemann, S.; Winnefeld, M. DNA methylation regulates lineage-specifying genes in primary lymphatic and blood endothelial cells. Angiogenesis 2012, 15, 317–329.
  31. Kato, Y.; Fujita, N.; Kunita, A.; Sato, S.; Kaneko, M.; Osawa, M.; Tsuruo, T. Molecular Identification of Aggrus/T1α as a Platelet Aggregation-inducing Factor Expressed in Colorectal Tumors. J. Biol. Chem. 2003, 278, 51599–51605.
  32. Kaneko, M.; Kato, Y.; Kunita, A.; Fujita, N.; Tsuruo, T.; Osawa, M. Functional Sialylated O-Glycan to Platelet Aggregation on Aggrus (T1α/Podoplanin) Molecules Expressed in Chinese Hamster Ovary Cells. J. Biol. Chem. 2004, 279, 38838–38843.
  33. Suzuki-Inoue, K.; Kato, Y.; Inoue, O.; Kaneko, M.K.; Mishima, K.; Yatomi, Y.; Yamazaki, Y.; Narimatsu, H.; Ozaki, Y. Involvement of the Snake Toxin Receptor CLEC-2, in Podoplanin-mediated Platelet Activation, by Cancer Cells. J. Biol. Chem. 2007, 282, 25993–26001.
  34. Christou, C.M.; Pearce, A.C.; Watson, A.A.; Mistry, A.R.; Pollitt, A.Y.; Fenton-May, A.E.; Johnson, L.A.; Jackson, D.G.; Watson, S.P.; O’Callaghan, C.A. Renal cells activate the platelet receptor CLEC-2 through podoplanin. Biochem. J. 2008, 411, 133–140.
  35. Kaneko, M.K.; Kato, Y.; Kameyama, A.; Ito, H.; Kuno, A.; Hirabayashi, J.; Kubota, T.; Amano, K.; Chiba, Y.; Hasegawa, Y.; et al. Functional glycosylation of human podoplanin: Glycan structure of platelet aggregation-inducing factor. FEBS Lett. 2007, 581, 331–336.
  36. Banerji, S.; Ni, J.; Wang, S.X.; Clasper, S.; Su, J.; Tammi, R.; Jones, M.; Jackson, D.G. LYVE-1, a New Homologue of the CD44 Glycoprotein, Is a Lymph-specific Receptor for Hyaluronan. J. Cell Biol. 1999, 144, 789–801.
  37. Lawrance, W.; Banerji, S.; Day, A.J.; Bhattacharjee, S.; Jackson, D.G. Binding of Hyaluronan to the Native Lymphatic Vessel Endothelial Receptor LYVE-1 Is Critically Dependent on Receptor Clustering and Hyaluronan Organization. J. Biol. Chem. 2016, 291, 8014–8030.
  38. Vondenhoff, M.F.; van de Pavert, S.; Dillard, M.E.; Greuter, M.; Goverse, G.; Oliver, G.; Mebius, R.E. Lymph sacs are not required for the initiation of lymph node formation. Development 2009, 136, 29–34.
  39. Onder, L.; Ludewig, B. A Fresh View on Lymph Node Organogenesis. Trends Immunol. 2018, 39, 775–787.
  40. A van de Pavert, S.; Olivier, B.J.; Goverse, G.; Vondenhoff, M.F.; Greuter, M.; Beke, P.; Kusser, K.; E Höpken, U.; Lipp, M.; Niederreither, K.; et al. Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat. Immunol. 2009, 10, 1193–1199.
  41. Vondenhoff, M.F.; Greuter, M.; Goverse, G.; Elewaut, D.; Dewint, P.; Ware, C.F.; Hoorweg, K.; Kraal, G.; Mebius, R.E. LTbetaR signaling induces cytokine expression and up-regulates lymphangiogenic factors in lymph node anlagen. J. Immunol. 2009, 182, 5439–5445.
  42. Hagerling, R.; Pollmann, C.; Andreas, M.; Schmidt, C.; Nurmi, H.; Adams, R.H.; Alitalo, K.; Andresen, V.; Schulte-Merker, S.; Kiefer, F. A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO J. 2013, 32, 629–644.
  43. Maruyama, K.; Miyagawa-Tomita, S.; Mizukami, K.; Matsuzaki, F.; Kurihara, H. Isl1-expressing non-venous cell lineage contributes to cardiac lymphatic vessel development. Dev. Biol. 2019, 452, 134–143.
  44. Gancz, D.; Raftrey, B.C.; Perlmoter, G.; Marin-Juez, R.; Semo, J.; Matsuoka, R.L.; Karra, R.; Raviv, H.; Moshe, N.; Addadi, Y.; et al. Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration. eLife 2019, 8, e44153.
  45. Stone, O.A.; Stainier, D.Y.R. Paraxial Mesoderm Is the Major Source of Lymphatic Endothelium. Dev. Cell 2019, 50, 247–255.e3.
  46. Chen, H.I.; Sharma, B.; Akerberg, B.N.; Numi, H.J.; Kivela, R.; Saharinen, P.; Aghajanian, H.; McKay, A.S.; Bogard, P.E.; Chang, A.H.; et al. The sinus venosus contributes to coronary vasculature through VEGFC-stimulated angiogenesis. Development 2014, 141, 4500–4512.
  47. Pichol-Thievend, C.; Betterman, K.L.; Liu, X.; Ma, W.; Skoczylas, R.; Lesieur, E.; Bos, F.L.; Schulte, D.; Schulte-Merker, S.; Hogan, B.M.; et al. A blood capillary plexus-derived population of progenitor cells contributes to genesis of the dermal lymphatic vasculature during embryonic development. Development 2018, 145, dev160184.
  48. Stanczuk, L.; Martinez-Corral, I.; Ulvmar, M.H.; Zhang, Y.; Lavina, B.; Fruttiger, M.; Adams, R.H.; Saur, D.; Betsholtz, C.; Ortega, S.; et al. cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels. Cell Rep. 2015, 10, 1708–1721.
  49. Mahadevan, A.; Welsh, I.C.; Sivakumar, A.; Gludish, D.W.; Shilvock, A.R.; Noden, D.M.; Huss, D.; Lansford, R.; Kurpios, N.A. The left-right Pitx2 pathway drives organ-specific arterial and lymphatic development in the intestine. Dev. Cell 2014, 31, 690–706.
  50. Gordon, E.J.; Rao, S.; Pollard, J.W.; Nutt, S.L.; Lang, R.A.; Harvey, N.L. Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation. Development 2010, 137, 3899–3910.
  51. Hutcheson, D.A.; Zhao, J.; Merrell, A.; Haldar, M.; Kardon, G. Embryonic and fetal limb myogenic cells are derived from developmentally distinct progenitors and have different requirements for beta-catenin. Genes Dev. 2009, 23, 997–1013.
  52. Motoike, T.; Markham, D.W.; Rossant, J.; Sato, T.N. Evidence for novel fate of Flk1+ progenitor: Contribution to muscle lineage. Genesis 2003, 35, 153–159.
  53. Paulissen, E.; Martin, B.L. Myogenic regulatory factors Myod and Myf5 are required for dorsal aorta formation and angiogenic sprouting. Dev. Biol. 2022, 490, 134–143.
  54. Aspelund, A.; Tammela, T.; Antila, S.; Nurmi, H.; Leppanen, V.M.; Zarkada, G.; Stanczuk, L.; Francois, M.; Makinen, T.; Saharinen, P.; et al. The Schlemm’s canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel. J. Clin. Investig. 2014, 124, 3975–3986.
  55. Kizhatil, K.; Ryan, M.; Marchant, J.K.; Henrich, S.; John, S.W. Schlemm’s canal is a unique vessel with a combination of blood vascular and lymphatic phenotypes that forms by a novel developmental process. PLoS Biol. 2014, 12, e1001912.
  56. Park, D.Y.; Lee, J.; Park, I.; Choi, D.; Lee, S.; Song, S.; Hwang, Y.; Hong, K.Y.; Nakaoka, Y.; Makinen, T.; et al. Lymphatic regulator PROX1 determines Schlemm’s canal integrity and identity. J. Clin. Investig. 2014, 124, 3960–3974.
  57. Truong, T.N.; Li, H.; Hong, Y.K.; Chen, L. Novel characterization and live imaging of Schlemm’s canal expressing Prox-1. PLoS ONE 2014, 9, e98245.
  58. Lewczuk, K.; Jablonska, J.; Konopinska, J.; Mariak, Z.; Rekas, M. Schlemm’s canal: The outflow ‘vessel’. Acta Ophthalmol. 2022, 100, e881–e890.
  59. Kim, J.; Park, D.Y.; Bae, H.; Park, D.Y.; Kim, D.; Lee, C.K.; Song, S.; Chung, T.Y.; Lim, D.H.; Kubota, Y.; et al. Impaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucoma. J. Clin. Investig. 2017, 127, 3877–3896.
  60. Kim, K.W.; Song, J.H. Emerging Roles of Lymphatic Vasculature in Immunity. Immune Netw. 2017, 17, 68–76.
  61. Bernier-Latmani, J.; Cisarovsky, C.; Demir, C.S.; Bruand, M.; Jaquet, M.; Davanture, S.; Ragusa, S.; Siegert, S.; Dormond, O.; Benedito, R.; et al. DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport. J. Clin. Investig. 2015, 125, 4572–4586.
  62. Bernier-Latmani, J.; Petrova, T.V. Intestinal lymphatic vasculature: Structure, mechanisms and functions. Nat. Rev. Gastroenterol. Hepatol. 2017, 14, 510–526.
  63. Kim, H.; Kataru, R.P.; Koh, G.Y. Inflammation-associated lymphangiogenesis: A double-edged sword? J. Clin. Investig. 2014, 124, 936–942.
  64. Lee, S.J.; Park, C.; Lee, J.Y.; Kim, S.; Kwon, P.J.; Kim, W.; Jeon, Y.H.; Lee, E.; Yoon, Y.S. Generation of pure lymphatic endothelial cells from human pluripotent stem cells and their therapeutic effects on wound repair. Sci. Rep. 2015, 5, 11019.
  65. Stacker, S.A.; Williams, S.P.; Karnezis, T.; Shayan, R.; Fox, S.B.; Achen, M.G. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat. Rev. Cancer 2014, 14, 159–172.
  66. Ren, B.; Cui, M.; Yang, G.; Wang, H.; Feng, M.; You, L.; Zhao, Y. Tumor microenvironment participates in metastasis of pancreatic cancer. Mol. Cancer 2018, 17, 108.
  67. Wong, B.W. Lymphatic vessels in solid organ transplantation and immunobiology. Am. J. Transplant. 2020, 20, 1992–2000.
  68. Kerjaschki, D.; Huttary, N.; Raab, I.; Regele, H.; Bojarski-Nagy, K.; Bartel, G.; Krober, S.M.; Greinix, H.; Rosenmaier, A.; Karlhofer, F.; et al. Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat. Med. 2006, 12, 230–234.
  69. Cimini, M.; Cannata, A.; Pasquinelli, G.; Rota, M.; Goichberg, P. Phenotypically heterogeneous podoplanin-expressing cell populations are associated with the lymphatic vessel growth and fibrogenic responses in the acutely and chronically infarcted myocardium. PLoS ONE 2017, 12, e0173927.
  70. DiMaio, T.A.; Wentz, B.L.; Lagunoff, M. Isolation and characterization of circulating lymphatic endothelial colony forming cells. Exp. Cell Res. 2016, 340, 159–169.
  71. Kwon, H.; Kwon, J.Y.; Song, J.; Maeng, Y.S. Decreased Lymphangiogenic Activities and Genes Expression of Cord Blood Lymphatic Endothelial Progenitor Cells (VEGFR3+/Pod+/CD11b+ Cells) in Patient with Preeclampsia. Int. J. Mol. Sci. 2021, 22, 4237.
  72. Huang, L.H.; Lavine, K.J.; Randolph, G.J. Cardiac Lymphatic Vessels, Transport, and Healing of the Infarcted Heart. JACC Basic Transl. Sci. 2017, 2, 477–483.
  73. Lupinski, R.W. Aortic fat pad and atrial fibrillation: Cardiac lymphatics revisited. ANZ J. Surg. 2009, 79, 70–74.
  74. Zhang, H.F.; Wang, Y.L.; Tan, Y.Z.; Wang, H.J.; Tao, P.; Zhou, P. Enhancement of cardiac lymphangiogenesis by transplantation of CD34+VEGFR-3+ endothelial progenitor cells and sustained release of VEGF-C. Basic Res. Cardiol. 2019, 114, 43.
  75. Campbell, K.T.; Curtis, M.B.; Massey, J.M.; Wysoczynski, K.; Hadley, D.J.; George, S.C.; Silva, E.A. Isolating and characterizing lymphatic endothelial progenitor cells for potential therapeutic lymphangiogenic applications. Acta Biomater. 2021, 135, 191–202.
  76. Abedin, M.; Tintut, Y.; Demer, L.L. Mesenchymal stem cells and the artery wall. Circ. Res. 2004, 95, 671–676.
  77. Conrad, C.; Niess, H.; Huss, R.; Huber, S.; von Luettichau, I.; Nelson, P.J.; Ott, H.C.; Jauch, K.W.; Bruns, C.J. Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo. Circulation 2009, 119, 281–289.
  78. Pu, Z.; Shimizu, Y.; Tsuzuki, K.; Suzuki, J.; Hayashida, R.; Kondo, K.; Fujikawa, Y.; Unno, K.; Ohashi, K.; Takefuji, M.; et al. Important Role of Concomitant Lymphangiogenesis for Reparative Angiogenesis in Hindlimb Ischemia. Arterioscler. Thromb. Vasc. Biol. 2021, 41, 2006–2018.
  79. Yamada, H.; Sakata, N.; Nishimura, M.; Tanaka, T.; Shimizu, M.; Yoshimatsu, G.; Kawakami, R.; Wada, H.; Sawamoto, O.; Matsumoto, S.; et al. Xenotransplantation of neonatal porcine bone marrow-derived mesenchymal stem cells improves murine hind limb ischemia through lymphangiogenesis and angiogenesis. Xenotransplantation 2021, 28, e12693.
  80. Nykanen, A.I.; Sandelin, H.; Krebs, R.; Keranen, M.A.; Tuuminen, R.; Karpanen, T.; Wu, Y.; Pytowski, B.; Koskinen, P.K.; Yla-Herttuala, S.; et al. Targeting lymphatic vessel activation and CCL21 production by vascular endothelial growth factor receptor-3 inhibition has novel immunomodulatory and antiarteriosclerotic effects in cardiac allografts. Circulation 2010, 121, 1413–1422.
  81. Dashkevich, A.; Raissadati, A.; Syrjala, S.O.; Zarkada, G.; Keranen, M.A.; Tuuminen, R.; Krebs, R.; Anisimov, A.; Jeltsch, M.; Leppanen, V.M.; et al. Ischemia-Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts. Am. J. Transplant. 2016, 16, 1160–1172.
  82. Zumsteg, A.; Baeriswyl, V.; Imaizumi, N.; Schwendener, R.; Ruegg, C.; Christofori, G. Myeloid cells contribute to tumor lymphangiogenesis. PLoS ONE 2009, 4, e7067.
  83. Muley, A.; Odaka, Y.; Lewkowich, I.P.; Vemaraju, S.; Yamaguchi, T.P.; Shawber, C.; Dickie, B.H.; Lang, R.A. Myeloid Wnt ligands are required for normal development of dermal lymphatic vasculature. PLoS ONE 2017, 12, e0181549.
  84. Zhang, B.; Yao, G.; Zhang, Y.; Gao, J.; Yang, B.; Rao, Z.; Gao, J. M2-polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma. Clinics 2011, 66, 1879–1886.
  85. Hos, D.; Bucher, F.; Regenfuss, B.; Dreisow, M.L.; Bock, F.; Heindl, L.M.; Eming, S.A.; Cursiefen, C. IL-10 Indirectly Regulates Corneal Lymphangiogenesis and Resolution of Inflammation via Macrophages. Am. J. Pathol. 2016, 186, 159–171.
  86. Karikoski, M.; Irjala, H.; Maksimow, M.; Miiluniemi, M.; Granfors, K.; Hernesniemi, S.; Elima, K.; Moldenhauer, G.; Schledzewski, K.; Kzhyshkowska, J.; et al. Clever-1/Stabilin-1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation. Eur. J. Immunol. 2009, 39, 3477–3487.
  87. Savetsky, I.L.; Ghanta, S.; Gardenier, J.C.; Torrisi, J.S.; Garcia Nores, G.D.; Hespe, G.E.; Nitti, M.D.; Kataru, R.P.; Mehrara, B.J. Th2 cytokines inhibit lymphangiogenesis. PLoS ONE 2015, 10, e0126908.
  88. Wen, J.H.; Li, D.Y.; Liang, S.; Yang, C.; Tang, J.X.; Liu, H.F. Macrophage autophagy in macrophage polarization, chronic inflammation and organ fibrosis. Front. Immunol. 2022, 13, 946832.
  89. Funes, S.C.; Rios, M.; Escobar-Vera, J.; Kalergis, A.M. Implications of macrophage polarization in autoimmunity. Immunology 2018, 154, 186–195.
  90. Zhang, Y.; Zhang, C.; Li, L.; Liang, X.; Cheng, P.; Li, Q.; Chang, X.; Wang, K.; Huang, S.; Li, Y.; et al. Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization. Cell Death Dis. 2021, 12, 109.
  91. Lee, J.Y.; Park, C.; Cho, Y.P.; Lee, E.; Kim, H.; Kim, P.; Yun, S.H.; Yoon, Y.S. Podoplanin-expressing cells derived from bone marrow play a crucial role in postnatal lymphatic neovascularization. Circulation 2010, 122, 1413–1425.
  92. Changming, W.; Xin, L.; Hua, T.; Shikun, W.; Qiong, X.; Zhigeng, Z.; Xueying, W. Monocytes can be induced to express lymphatic phenotypes. Lymphology 2011, 44, 48–53.
  93. Li, B.; Pozzi, A.; Young, P.P. TNFalpha accelerates monocyte to endothelial transdifferentiation in tumors by the induction of integrin alpha5 expression and adhesion to fibronectin. Mol. Cancer Res. 2011, 9, 702–711.
  94. David Dong, Z.M.; Aplin, A.C.; Nicosia, R.F. Regulation of angiogenesis by macrophages, dendritic cells, and circulating myelomonocytic cells. Curr. Pharm. Des. 2009, 15, 365–379.
  95. Zhigeng, Z.; Xin, L.; Yanling, Z.; Qiong, X.; Zhaolin, Z.; Lu, C.; Yaqian, S.; Cailing, L.; Shikun, W.; Hua, T. Transdifferentiated Monocytes: A Novel Source of Lymphatic Endothelial-like Cells. Lymphology 2017, 50, 73–83.
  96. Hu, L.R.; Pan, J. Adipose-derived stem cell therapy shows promising results for secondary lymphedema. World J. Stem Cells 2020, 12, 612–620.
  97. Li, Z.J.; Yang, E.; Li, Y.Z.; Liang, Z.Y.; Huang, J.Z.; Yu, N.Z.; Long, X. Application and prospect of adipose stem cell transplantation in treating lymphedema. World J. Stem Cells 2020, 12, 676–687.
  98. Ogino, R.; Hayashida, K.; Yamakawa, S.; Morita, E. Adipose-Derived Stem Cells Promote Intussusceptive Lymphangiogenesis by Restricting Dermal Fibrosis in Irradiated Tissue of Mice. Int. J. Mol. Sci. 2020, 21, 3885.
  99. Li, C.Y.; Wu, X.Y.; Tong, J.B.; Yang, X.X.; Zhao, J.L.; Zheng, Q.F.; Zhao, G.B.; Ma, Z.J. Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno-free conditions for cell therapy. Stem Cell Res. Ther. 2015, 6, 55.
  100. Yang, Y.; Li, X.B.; Li, Y.; Li, T.X.; Li, P.; Deng, G.M.; Guo, Q.; Zhou, X.; Chen, X.H. Extracellular Vesicles Derived From Hypoxia-Conditioned Adipose-Derived Mesenchymal Stem Cells Enhance Lymphangiogenesis. Cell Transplant. 2022, 31, 9636897221107536.
  101. Laschke, M.W.; Spater, T.; Menger, M.D. Microvascular Fragments: More Than Just Natural Vascularization Units. Trends Biotechnol. 2021, 39, 24–33.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Others
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Rong Mou ,
Kai Chen
,
Pengwei Zhu
, Qingbo Xu , Liang Ma
View Times: 779
Revisions: 2 times (View History)
Update Date: 30 Dec 2022
Table of Contents
    Notice
    You are not a member of the advisory board for this topic. If you want to update advisory board member profile, please contact office@encyclopedia.pub.
    OK
    Confirm
    Only members of the Encyclopedia advisory board for this topic are allowed to note entries. Would you like to become an advisory board member of the Encyclopedia?
    Yes
    No
    ${ textCharacter }/${ maxCharacter }
    Submit
    Cancel
    There is no comment~
    ${ textCharacter }/${ maxCharacter }
    Submit
    Cancel
    ${ selectedItem.replyTextCharacter }/${ selectedItem.replyMaxCharacter }
    Submit
    Cancel
    Confirm
    Are you sure to Delete?
    Yes No
    Academic Video Service
    Feedback