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Wong, A.; , . Lymphatic Tissue Bioengineering based on Stem Cells. Encyclopedia. Available online: https://encyclopedia.pub/entry/23606 (accessed on 04 July 2024).
Wong A,  . Lymphatic Tissue Bioengineering based on Stem Cells. Encyclopedia. Available at: https://encyclopedia.pub/entry/23606. Accessed July 04, 2024.
Wong, Alex, . "Lymphatic Tissue Bioengineering based on Stem Cells" Encyclopedia, https://encyclopedia.pub/entry/23606 (accessed July 04, 2024).
Wong, A., & , . (2022, May 31). Lymphatic Tissue Bioengineering based on Stem Cells. In Encyclopedia. https://encyclopedia.pub/entry/23606
Wong, Alex and . "Lymphatic Tissue Bioengineering based on Stem Cells." Encyclopedia. Web. 31 May, 2022.
Lymphatic Tissue Bioengineering based on Stem Cells
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This entry is adapted from the peer-reviewed paper 10.3390/bioengineering9040162

Lymphedema is characterized by progressive and chronic tissue swelling and inflammation from local accumulation of interstitial fluid due to lymphatic injury or dysfunction. It is a debilitating condition that significantly impacts a patient’s quality of life, and has limited treatment options. With better understanding of the molecular mechanisms and pathophysiology of lymphedema and advances in tissue engineering technologies, lymphatic tissue bioengineering and regeneration have emerged as a potential therapeutic option for postsurgical lymphedema. Various strategies involving stem cells, lymphangiogenic factors, bioengineered matrices and mechanical stimuli allow more precisely controlled regeneration of lymphatic tissue at the site of lymphedema without subjecting patients to complications or iatrogenic injuries associated with surgeries. 

Stem Cells Lymphatic Tissue Treatment lymphedema lymphangiogenesis retinoic acid VEGF-C

1. Stem Cells

Stem cells are characterized by their capacity for self-renewal and multilineage differentiation. Based on their differentiation potential, stem cells are divided into totipotent, pluripotent, multipotent, oligopotent, and unipotent stem cells [1]. Totipotent stem cells refer to zygote and blastomeres which can form all the cell types in a body and the placenta. The pluripotent stem cells include embryonic stem cells (ESC) and induced pluripotent stem cells (iPSCs) that can give rise to all the cell types that make up the body. Multipotent stem cells are found in most tissues and differentiate into cells from a single germ layer. Mesenchymal stem cells (MSCs) are the most recognized multipotent stem cells that can be derived from a variety of tissue including bone marrow, adipose tissue, bone, Wharton’s jelly, umbilical cord blood, and peripheral blood. These cells tend to turn into mesoderm-derived tissue such as adipose tissue, bone, cartilage, and muscle. Oligopotent stem cells can self-renew and form two or more lineages within a specific tissue. Hematopoietic stem cells are a typical example of oligopotent stem cells, as they can differentiate into both myeloid and lymphoid lineages. Unipotent stem cells can self-renew and differentiate into only one specific cell type and form a single lineage.

2. Embryonic Stem Cells (ESCs)

Embryonic stem cells are obtained from the inner cell mass of the blastocyst that is three to five days old. Embryonic stem cells can give rise to every cell type in the fully formed body, but not the placenta and umbilical cord. Lymphatic endothelial cells were successfully differentiated from VEGFR-2+ embryonic stem cells at day 3 on OP9 stromal cells. These endothelial cells were defined by the expression of LEC-specific markers, Prox1, VEGFR-3, Podoplanin, and LYVE-1 [2]. Kono et al. used 2 successive steps for LEC differentiation from ESCs. VEGFR-2+ E-cad− mesodermal cells were first generated and enriched from ESCs. ESC-derived purified VEGFR-2+ cells were then cocultured with OP9 Cells onto type IV collagen-coated dishes in the presence of VEGF-C and Ang-1. However, the molecular basis of LEC induction activity by OP9 cells remains to be elucidated. The addition of VEGF-A and VEGF-C to murine ESCs and LECs led to the formation of embryoid bodies (EBs) at day 18. ESCs are collected from early-stage embryos, which only consists of 100–200 cells. The scarce source of human oocytes combined time-consuming processes greatly limits their widespread use. The ethical debate about using embryos needs to be considered as well. Moreover, as embryonic cells are allogenic, they pose an immunologic barrier to the patient.

3. Human Induced Pluripotent Stem Cells (hiPSCs)

Induced pluripotent stem cells (iPSCs) share similar characteristics with ESCs and can differentiate into LECs [3]. iPSCs are usually made from skin or blood cells. Researchers described an effective protocol to convert hiPSCs into cells similar to cord-blood endothelial colony-forming cells (CB-ECFCs), vascular endothelial cells and smooth muscle cells [1][4]. Studies showed therapeutic efficacy of hiPSC-derived endothelial cells in pre-clinical models of cardiovascular disease [2][3]. The hiPSC-ECs generated from the differentiation of hiPSCs using VEGF-A and bone morphogenetic protein-4 were purified based on positive expression of CD31. Rufaihah et al. demonstrated that FACS purification of CD31+ hiPSC-ECs produced a diverse population of ECs. Given heterogeneity of hiPSC-derived endothelial cells, researchers induced differentiation of hiPSC-derived endothelial cells to lymphatic phenotype using VEGF-C and angiopoietin-1 [5]. VEGF-C, which acts on the VEGFR3 receptor, promotes migration of lymphatic endothelial progenitors from the vein. Ang-1 acts through the receptor tyrosine kinase, Tie-2 in regulating lymphatic vessel formation, sprouting, and lymphatic endothelial proliferation. High VEGF-A and VEGF-C concentrations with supplementation of Ang-1 in the medium promote the specification to lymphatic CD31+ hiPSC-ECs. Lee et al. found that an OP9-assisted culture system reinforced by the addition of VEGF-A, VEGF-C, and EGF most efficiently generated LECs, which were then isolated via FACS-sorting with LYVE-1 and Podoplanin [6]. These hiPSC-derived LYVE-1 + Podoplanin + cells exhibited a pure committed LEC phenotype, formed new lymphatic vessels, and expressed lymphangiogenic factors at high levels. These hiPSC-derived LECs improve wound healing by promoting lymphatic neovascularization through both lymphvasculogenesis and lymphangiogenesis. However, since xeno-free and well-defined culture conditions are ideal for clinical application, this approach of LEC differentiation requiring co-culture with mouse OP9 stromal cells may not be suitable [6][7].

4. Multipotent Adult Progenitor Cells (MAPCs)

Multipotent Adult Progenitor Cells (MAPC) are non-hematopoietic cells found in bone marrow stroma, which play a role in the maintenance of the hematopoietic stem cell niche. While these cells meet the International Society for Cell Therapy (ISCT) criteria for MSCs, they were perceived to be a more biologically primitive population than classical MSCs and had greater differentiation potential [5]. Bone marrow derived multipotent adult progenitor cells (MAPCs) have multi-lineage differentiation potential. Beerens et al. reported that, in vitro, MAPCs showed potential to differentiate down the lymphatic endothelial lineage. Culturing MAPCs with VEGF-A results in a heterogeneous mixture of arterial, venous, and lymphatic endothelial cells [8]. Unlike hiPSCs, exposure to VEGF-C did not increase lymphatic differentiation. In addition, MAPCs promoted lymphangiogenesis in vivo and restored lymph drainage across skin flaps by stimulating capillary and pre-collector vessel regeneration. Considering the proangiogenic effect of MAPC may affect tumor growth or metastasis, the proangiogenic response should be sufficiently balanced and locally controlled.

5. Adipose Tissue-Derived Stem Cells (ADSCs)

Adipose tissue-derived stem cells (ADSCs) are multipotent stem cells within adipose tissue and a promising source for lymphangiogenesis [6]. ADSCs have two lymphangiogenic mechanisms: paracrine secretion and direct differentiation into lymphatic endothelial cells [9]. Studies have shown LEC differentiation from human ADSCs by lentiviral Prox1 overexpression as well as IL-7 through AKT pathways [8][10]. In vivo studies on mouse lymphedema models demonstrated that ADSC injection resulted in greater lymphatic capillary density, tissue expression of VEGF-C, plasma levels of VEGF-C, and higher recovery from lymphedema [9]. When ADSC injection was combined with vascularized lymph node transplant, ADSCs promoted an increase in lymphatic vessels and preservation of transplanted lymph nodes [11]. ADSCs have been used clinically. A single injection of ADSCs into the axillary region together with a scar releasing fat graft procedure improved patient-reported outcomes and reduced use of conservative management in 10 BCRL patients at a 1-year follow-up. However, no significant changes in volume and quantitative lymphoscintigraphy on the lymphedema affected arms were noted at one year follow-up [12]. Nonetheless, as abundant and autologous sources of stem cells, ADSCs show the potential to be used in lymphatic tissue engineering and regeneration. Further studies are needed to establish standardized protocols and explore long-term outcomes.

6. Hematopoietic Stem Cells (HSCs)

Hematopoietic stem cells (HSCs) are a type of oligopotent stem cell that differentiate into cells of the blood and immune system. Adult mouse bone marrow derived HSCs give rise to functional vascular endothelial cells that express CD31, produce von Willebrand factor, and take up low density lipoprotein [5][6][9][13]. Jiang et al. showed that adult hematopoietic stem cells can give rise to LECs that integrate into lymphatic vessels of normal tissues and in newly formed tumors [14]. It is not well understood whether HSC-derived LECs potentiate lymphangiogenesis in tumors and therefore will need further studies.

7. Endothelial Colony-Forming Cells (ECFCs)

Endothelial colony-forming cells (ECFCs) were isolated from adult human peripheral blood and noted to express blood vascular or lymphatic-specific [15]. Even though a majority of ECFCs expressed high levels of VEGFR-1, two of the clones (ECFC L1 and L2) expressed very low levels of VEGFR-1 but high levels of VEGFR-3, podoplanin, LYVE-1, and prox-1. The lymphatic ECFCs responded to VEGF-C and VEGF-A while the blood ECFCs only responded to VEGF-A. Lymphatic ECFCs expressed higher levels of Wnt 5a and Wnt 5b, Notch 3 and Jagged 1, suggesting that Notch signaling during development of endothelial precursors could be playing a role in their lymphatic specification.
Growing evidence has shown the regenerative potential of stem cells in the tissue bioengineering, and a variety of stem cells including embryonic, induced pluripotent, mesenchymal, and others, have been studied. Despite possessing great pluripotency and proliferative capacity, several challenges in altering the state of cells limit their widespread clinical translation of pluripotent stem cells [16]. Efficient differentiation of stem cells and reliable maintenance of the viability and potency of differentiated cells during the process are critical obstacles that need to be addressed [17]. Another concern associated with stem cells is safety. Inducing differentiation of stem cells into a lymphatic endothelial cell type with 100% efficiency is difficult and a small fraction of undifferentiated cells may remain, which can lead to neoplastic development [16]. iPSCs and adult progenitor cells overcome ethical and immunological barriers of embryonic stem cells and provide a more stable tissue source. Given the ease of availability and abundance, they represent an attractive option for lymphatic tissue engineering [6].
The limitations of stem cells can be overcome with bioengineering technology. Pro-lymphangiogenic factors can guide the fate of stem cells and their regenerative potential. Biomaterials provide a supportive microenvironment for cells to proliferate and differentiate. They can be engineered with a specific mechanical and biochemical property to improve proliferation and differentiation capacity and viability, and to preserve stem cell function.

References

  1. Kolios, G.; Moodley, Y. Introduction to stem cells and regenerative medicine. Respiration 2013, 85, 3–10.
  2. Kono, T.; Kubo, H.; Shimazu, C.; Ueda, Y.; Takahashi, M.; Yanagi, K.; Fujita, N.; Tsuruo, T.; Wada, H.; Yamashita, J.K. Differentiation of lymphatic endothelial cells from embryonic stem cells on OP9 stromal cells. Arterioscler. Thromb. Vasc. Biol. 2006, 26, 2070–2076.
  3. Takahashi, K.; Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126, 663–676.
  4. Griffith, L.G.; Swartz, M.A. Capturing complex 3D tissue physiology in vitro. Nat. Rev. Mol. Cell Biol. 2006, 7, 211–224.
  5. Khan, R.S.; Newsome, P.N. A Comparison of Phenotypic and Functional Properties of Mesenchymal Stromal Cells and Multipotent Adult Progenitor Cells. Front. Immunol. 2019, 10, 1952.
  6. Qi, S.; Pan, J. Cell-based therapy for therapeutic lymphangiogenesis. Stem Cells Dev. 2015, 24, 271–283.
  7. Park, K.E.; Allam, O.; Chandler, L.; Mozzafari, M.A.; Ly, C.; Lu, X.; Persing, J.A. Surgical management of lymphedema: A review of current literature. Gland Surg. 2020, 9, 503–511.
  8. Deng, J.; Dai, T.; Sun, Y.; Zhang, Q.; Jiang, Z.; Li, S.; Cao, W. Overexpression of Prox1 Induces the Differentiation of Human Adipose-Derived Stem Cells into Lymphatic Endothelial-Like Cells In Vitro. Cell. Reprogram. 2017, 19, 54–63.
  9. Forte, A.J.; Boczar, D.; Sarabia-Estrada, R.; Huayllani, M.T.; Avila, F.R.; Torres, R.A.; Guliyeva, G.; Aung, T.; Quiñones-Hinojosa, A. Use of adipose-derived stem cells in lymphatic tissue engineering and regeneration. Arch. Plast. Surg. 2021, 48, 559–567.
  10. Sun, Y.; Lu, B.; Deng, J.; Jiang, Z.; Cao, W.; Dai, T.; Li, S. IL-7 enhances the differentiation of adipose-derived stem cells toward lymphatic endothelial cells through AKT signaling. Cell Biol. Int. 2019, 43, 394–401.
  11. Hayashida, K.; Yoshida, S.; Yoshimoto, H.; Fujioka, M.; Saijo, H.; Migita, K.; Kumaya, M.; Akita, S. Adipose-Derived Stem Cells and Vascularized Lymph Node Transfers Successfully Treat Mouse Hindlimb Secondary Lymphedema by Early Reconnection of the Lymphatic System and Lymphangiogenesis. Plast. Reconstr. Surg. 2017, 139, 639–651.
  12. Toyserkani, N.M.; Jensen, C.H.; Tabatabaeifar, S.; Jørgensen, M.G.; Hvidsten, S.; Simonsen, J.A.; Andersen, D.C.; Sheikh, S.P.; Sørensen, J.A. Adipose-derived regenerative cells and fat grafting for treating breast cancer-related lymphedema: Lymphoscintigraphic evaluation with 1 year of follow-up. J. Plast. Reconstr. Aesthet. Surg. 2019, 72, 71–77.
  13. Bailey, A.S.; Jiang, S.; Afentoulis, M.; Baumann, C.I.; Schroeder, D.A.; Olson, S.B.; Wong, M.H.; Fleming, W.H. Transplanted adult hematopoietic stems cells differentiate into functional endothelial cells. Blood 2004, 103, 13–19.
  14. Campisi, C.; Bellini, C.; Campisi, C.; Accogli, S.; Bonioli, E.; Boccardo, F. Microsurgery for lymphedema: Clinical research and long-term results. Microsurgery 2010, 30, 256–260.
  15. 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.
  16. Kwon, S.G.; Kwon, Y.W.; Lee, T.W.; Park, G.T.; Kim, J.H. Recent advances in stem cell therapeutics and tissue engineering strategies. Biomater. Res. 2018, 22, 36.
  17. Madl, C.M.; Heilshorn, S.C.; Blau, H.M. Bioengineering strategies to accelerate stem cell therapeutics. Nature 2018, 557, 335–342.
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Subjects: Cell & Tissue Engineering
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