Review: Biomimetic nanofibers in the ex vivo expansion of cord blood-derived hematopoietic stem cells

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Cherese Winstead Lewis Lott Kimberley Milligan Lindsey Hyppolite


This review summarizes current strategies in the development of advanced nanofibrous polymer-based scaffolds via electrospinning, their applications in mimicking the extracellular matrix, and the use of polymer nanofibers to deliver growth factors or small molecules for ex vivo expansion of HSCs. Hematopoietic stem cell (HSC) transplantation has become the standard of care for patients with hematologic cancers, anemia, and a variety of other malignant and non-malignant disorders. Although mobilized peripheral blood (MPB) has become a preferred source of HSCs for transplants, bone marrow (BM) and umbilical cord blood (UCB) are also frequently utilized. Regardless of source, Regardless of source, HSC transplantation suffers from low cell doses. Therefore, methods to increase the cell dose while maintaining the progenitor phenotype, especially the CD34+ progenitor cells, would have a significant clinical impact. Ex vivo expansion of HSCs prior to transplantation is one approach that offers tremendous promise for increasing cell doses and improving clinical outcomes. Many ex vivo strategies have been developed within the last decade in order to address the issue of low cell dose, with more or less success, mainly determined by the degree of difficulty related with maintaining HSCs self-renewal and stemness properties after long-term expansion. Here, we report the current progress of nanofibrous scaffolds for the ex vivo expansion of hematopoietic stem cells (HSCs). In this review, we present the technique of electrospinning for nanofibrous scaffolds, focusing mainly on preparation methods, materials (synthetic, natural, and hybrid polymers), and surface-structural modifications. The variables of nanofiber processing parameters and its impact on the nanofiber assembly is reported as well as the effect of the solution parameters on the structural morphology of the fabricated nanofibers. Critical features of fabricated nanofibers such as porous structure and high specific surface area are addressed, but more importantly the necessity of mimicking the intrinsic properties of the native in vivo microenvironment of the extracellular matrix (ECM). Researchers have been largely successful in replicating the diverse nature of the ECM through the incorporation of small molecules, growth factors, and signaling molecules into 3D scaffolds to generate biomimetic hierarchical structures. Harnessing the potential of the stem cell niche forms the basis of clinical therapy in the ex vivo expansion of cord blood-derived hematopoietic stem cells. As reviewed in this article, advances in nanofiber ex vivo approaches based upon emerging biomaterials opens new doors for artificial niches. Scientific evidence provided in this review verifies that the nanofiber niche provides an ideal mimic of the physical microenvironment of HSCs thereby offering great potential for clinical applications.

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WINSTEAD, Cherese et al. Review: Biomimetic nanofibers in the ex vivo expansion of cord blood-derived hematopoietic stem cells. Medical Research Archives, [S.l.], v. 8, n. 7, july 2020. ISSN 2375-1924. Available at: <>. Date accessed: 08 aug. 2020. doi:
Review Articles


1. Lu J, Aggarwal R, Pompili VJ, Das H: A novel technology for hematopoietic stem cell expansion using combination of nanofiber and growth factors, Recent Pat Nanotechnology 2010; 4(2):125-35.
2. Morgan RA, Gray D, Lomova A, Kohn DB: Hematopoietic Stem Cell Gene Therapy: Progress and Lessons Learned. Cell Stem Cell 2017;21(5):574–590. doi:10.1016/j.stem.2017.10.010
3. Walters MC. Update of hematopoietic cell transplantation for sickle cell disease. Current Opinion in Hematology 2015; 22:227–233. doi: 10.1097/MOH.0000000000000136.
4. Bryder D, Rossi DJ, and Weissman IL: Hematopoietic stem cells: the paradigmatic tissue-specific stem cell. Am J Pathol. 2006; 169: 338–346.
5. Bone BP: The hematopoietic niche: a tale of two stem cells. Blood 2011; 117: 5281–5288
6. Panch SR, Szymanski J, Savani BN, Stroncek DF. Sources of Hematopoietic Stem and Progenitor Cells and Methods to Optimize Yields for Clinical Cell Therapy, Biology of Blood and Marrow Transplantation 2017; 23:8, 1241-1249.
7. Watts KL, Adair J, Kiem HP: Hematopoietic stem cell expansion and gene therapy. Cytotherapy. 2011; 13:10, 1164–1171. doi:10.3109/14653249.2011.620748
8. Zhang P, ZhangC., Li J. : The physical microenvironment of hematopoietic stem cells and its emerging roles in engineering applications. Stem Cell Res Ther 2019; 10: 327.
9. Naldini L: Ex vivo gene transfer and correction for cell-based therapies (Review) Nat Rev Genet. 2011; 12: 301–15.
10. Roselli EA, Mezzadra R, Frittoli MC, Maruggi G, Biral E, Mavilio F: Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients. EMBO molecular medicine. 2010; 2:315–28.
11. Mehta RS, Rezvani K, Olson A: Novel Techniques for Ex Vivo Expansion of Cord Blood: Clinical Trials. Front Med 2015; 2:89. doi:10.3389/fmed.2015.00089
12. Gragert L, Eapen M, Williams E, Freeman J, Spellman S, Baitty R: HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med 2014; 371:339 48.10.1056/NEJMsa1311707
13. Kurtzberg J, Laughlin M, Graham ML, Smith C, Olson JF, Halperin EC: Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med 1996; 335:157–66.
14. Leena M, Barade A, Rana D, Dhand C, Ramakrishna S, Ramalingam M: Nanofiber composites in biomolecular delivery, Nanofiber Composites for Biomedical Applications 2017; 225-252
15. Nikiforow, S., Ritz, J. Dramatic Expansion of HSCs: New Possibilities for HSC Transplants? Cell Stem Cell 2016; 18, (1), 10-12.
16. Broxmeyer, HE: Enhancing the efficacy of engraftment of cord blood for hematopoietic cell transplantation. Transfusion and Apheresis Science 2016; 54:3, 364-372.
17. Papa, L, Djedaini, M, Hoffman, R: Ex Vivo Expansion of Hematopoietic Stem Cells from Human Umbilical Cord Blood-derived CD34+ Cells Using Valproic Acid. J. Vis. Exp. 2019; (146), e59532, doi:10.3791/59532
18. Frantz C, Stewart KM, Weaver VM: The extracellular matrix at a glance. J Cell Sci. 2010; 123:24, 4195–4200. doi:10.1242/jcs.023820
19. Badylak SF: The extracellular matrix as a biologic scaffold material. Biomaterials 2007; 28, 3587-3593.
20. Bosman FT, Stamenkovic I: Functional structure and composition of the extracellular matrix. J. Pathol. 2003; 200, 423-428.
21. Iozzo RV, Murdoch AD: Proteoglycans of the extracellular environment: clues from the gene and protein side offer novel perspectives in molecular diversity and function. FASEB J. 1996; 10, 598-614.
22. Kleinman HK, Martin GR: Matrigel: basement membrane matrix with biological activity. Semin. Cancer Biol. 2005; 15, 378-386.
23. Schaefer L, Schaefer RM: Proteoglycans: from structural compounds to signaling molecules. Cell Tissue Res. 2010; 339, 237-246.
24. Jarvelainen H, Sainio A, Koulu M, Wight TN, Penttinen R : Extracellular matrix molecules: potential targets in pharmacotherapy. Pharmacol. Rev. 2009; 61, 198-223.
25. Nemati S, Kim SJ, Shin YM, Shin H : Current progress in application of polymeric nanofibers to tissue engineering. Nano Converg. 2019;6(1):36. Published 2019 Nov 8. doi:10.1186/s40580-019-0209-y
26. Lee-Thedieck C, Rauch N, Fiammengo R, Klein G, Spatz JP: Impact of substrate elasticity on human hematopoietic stem and progenitor cell adhesion and motility. Journal of Cell Science, 2012; 125 (16), 3765-3775.
27. Wilson A, Trumpp A : Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 2006; 6: 93–106 .
28. Watt FM, Hogan BL: Out of Eden: stem cells and their niches. Science 2000; 287, 1427–1430.
29. Kennedy KM, Bhaw-Luximon A, Jhurry D: Cell-matrix mechanical interaction in electrospun polymeric scaffolds for tissue engineering: Implications for scaffold design and performance, Acta Biomaterialia 2017; 50: 1, 41-55.
30. Fuchs, E, Tumbar T, Guasch G: Socializing with the neighbors: stem cells and their niche. Cell 2004; 116, 769–778.
31. Yousefi AM, James PF, Akbarzadeh R, Subramanian A, Flavin C, Oudadesse H: Prospect of stem cells in bone tissue engineering: A Review. Stem Cells Int. 2016; 2016:6180487. doi:10.1155/2016/6180487
32. Harrison RH, St-Pierre JP, Stevens MM: Tissue engineering and regenerative medicine: a year in review. Tissue Engineering Part B: Reviews. 2014;20(1):1–16. doi: 10.1089/ten.teb.2013.0668.
33. Jiang T, Carbone E, Lo K, Laurencin CT: Electrospinning of polymer nanofibers for tissue regeneration. Progress in Polymer Science 2014; 46, 1-24. 10.1016/j.progpolymsci.2014.12.001.
34. Xiumei M, Sun B, Tong W, Li S: Electrospun Nanofibers for Tissue Engineering; Electrospinning: Nanofabrication and Applications 2019; 719-734. 10.1016/B978-0-323-51270-1.00024-8.
35. Gvaramia D, Müller E, Müller K, Atallaha P, Combined influence of biophysical and biochemical cues on maintenance and proliferation of hematopoietic stem cells. Biomaterials 2017; Volume 138, 108-117.
36. Li WJ, Tuan RS. Fabrication and application of nanofibrous scaffolds in tissue engineering. Curr Protoc Cell Biol. 2009; Chapter 25:Unit–25.2. doi:10.1002/0471143030.cb2502s42
37. Doshi J, Reneker DH. Electrospinning Process and Applications of Electrospun Fibers. J Electrostatics. 1995; 35:151–160.
38. Li WJ, Mauck RL, Tuan RS. Electrospun nanofibrous scaffolds: production, characterization, and applications for tissue engineering and drug delivery. J Biomed Nanotechnology. 2005;1:259–275.
39. Li WJ, Shanti RM, Tuan RS. Electrospinning technology for nanofibrous scaffolds in tissue engineering. Nanotechnologies for the life sciences. Tissue, cell, and organ engineering. 2006; vol 9, 135–187.
40. Sill TJ, von Recum HA, Electrospinning: Applications in drug delivery and tissue engineering, Biomaterials 2008; 29: 13, 1989-2006.
41. Bhardwaj N, Kundu SC: Electrospinning: A fascinating fiber fabrication technique
Biotechnology Advances 2010; 28:3, 325-347.
42. Hu X, Liu S, Zhou G, Huang Y: Electrospinning of polymeric nanofibers for drug delivery applications. Journal of Controlled Release 2014; 185:10, 12-21.
43. Ghasemi-Mobarakeh L, Prabhakaran MP, Tian L, Shamirzaei-Jeshvaghani E, Dehghani L, Ramakrishna S. Structural properties of scaffolds: Crucial parameters towards stem cells differentiation. World J Stem Cells. 2015;7(4):728–744. doi:10.4252/wjsc.v7.i4.728
44. Almetwally AA, El-Sakhawy M, Elshakankery MH, Kasem MH: Technology of nano-fibers: Production techniques and properties - Critical review. Journal of the Textile Association 2017; 78. 5-14.
45. Beachley V, Wen X: Polymer nanofibrous structures: Fabrication, biofunctionalization, and cell interactions. Progress in Polymer Science 2010; 35:7, 868-892.
46. Salas C: Solution electrospinning of nanofibers. Electrospun Nanofibers 2017; 73-108.
47. Zhang YZ, Su B, Venugopal J, Ramakrishna S, Lim CT. Biomimetic and bioactive nanofibrous scaffolds from electrospun composite nanofibers. Int J Nanomedicine. 2007;2(4):623–638.
48. Agarwal S, Jiang S: Nanofibers and Elecrospinning. Kobayashi S, Mullen K, editors. Berlin: Springer; 2015.
49. Yoo HS, Kim TG, Park TG: Surface-functionalized electrospun nanofibers for tissue engineering and drug delivery. Advanced Drug Delivery Reviews 2009; 61:12, 1033-1042.
50. Chua KN, Chai C, Lee PC: Surface-aminated electrospun nanofibers enhance adhesion and expansion of human umbilical cord blood hematopoietic stem/progenitor cells. Biomaterials 2006; 27:36, 6043-6051.
51. Safaeijavan R, Soleimani M, Divsalar A, Eidi A, Ardeshirylajimi A: Comparison of random and aligned PCL nanofibrous electrospun scaffolds on cardiomyocyte differentiation of human adipose-derived stem cells. Iran J Basic Med Sci. 2014;17(11):903–911.
52. Wang X, Ding B, Li B: Biomimetic electrospun nanofibrous structures for tissue engineering. Materials Today 2013; 16: 6, 229-241.
53. Sidney LE, Branch MJ, Dunphy SE, Dua HS, Hopkinson A: Concise review: evidence for CD34 as a common marker for diverse progenitors. Stem Cells. 2014; 32: 1380-1389.
54. Adams GB, Scadden DT: The hematopoietic stem cell in its place. Nat Immunol 2006; 7: 333-337. DOI: 10.1038/ni1331
55. Salati S, Zini R, Bianchi E, Testa A, Mavilio F: Role of CD34 antigen in myeloid differentiation of human hematopoietic progenitor cells. Stem Cells. 2008; 26: 950-959.
56. Heimfeld S. Bone marrow transplantation: how important is CD34 cell dose in HLA-identical stem cell transplantation? Leukemia. 2003; 17: 856-858.
57. Kita K, Xiu F, Jeschke MG: Ex vivo expansion of hematopoietic stem and progenitor cells: Recent advances, World J Hematol. 2014; 3(2): 18-28. doi: 10.5315/wjh.v3.i2.18
58. Tung S, Parmar S, Robinson S, De Lima M, Shpall E : Ex vivo expansion of umbilical cord blood for transplantation. Best Pract Res Clin Haematol 2010; 23: 245-257.
59. Tajer P, Pike-Overzet K, Arias S, Havenga M, Staal FJT: Ex Vivo Expansion of Hematopoietic Stem Cells for Therapeutic Purposes: Lessons from Development and the Niche. Cells. 2019;8(2):169. doi:10.3390/cells8020169
60. Bari S, Seah KK, Poon Z, Cheung AM, Fan X: Expansion and homing of umbilical cord blood hematopoietic stem and progenitor cells for clinical transplantation. Biol Blood Marrow Transplant 2015; 21: 1008-1019.
61. Dahlberg A, Delaney C, Bernstein ID : Ex vivo expansion of human hematopoietic stem and progenitor cells. Blood 2011; 117: 6083-6090.
62. Giarratana MC, Kobari L, Lapillonne H, Chalmers D, Kiger L: Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells. Nat Biotechnol. 2005; 23: 69-74.
63. Eskandari F, Allahverdi A, Nasiri H: Nanofiber Expansion of Umbilical Cord Blood Hematopoietic Stem Cells. Iran J Ped Hematol Oncol. 2015;5(4):170–178.
64. Chou S, Chu P, Hwang W, Lodish H : Expansion of human cord blood hematopoietic stem cells for transplantation. Cell Stem Cell 2010; 7: 427-428.
65. Flores-Guzmán P, Fernández-Sánchez V, Mayani H: Concise review: Ex vivo expansion of cord blood‐derived hematopoietic stem and progenitor cells: Basic principles, experimental approaches, and impact in regenerative medicine. Stem Cells Transl Med 2013; 2: 830-838.
66. Baron F, Ruggeri A, Nagler A : Methods of ex vivo expansion of human cord blood cells: Challenges, successes and clinical implications. Expert Rev Hematol 2016; 9: 297-314.
67. Lu J, Aggarwal R, Pompili VJ, Das H: A Novel Technology for Hematopoietic Stem Cell Expansion Using Combination of Nanofiber and Growth Factors. Recent Patents on Nanotechnology 2010; 4:2 DOI : 10.2174/187221010791208777
68. Fischer SE, Ma Y, Smith C, Sodha A, Zhao Y: Cell Collection and Processing: Towards the Development of a Closed, Nanofiber-Based Culture System for Clinical Expansion of Cord Blood-Derived CD34+ Cells Blood 2012; 120:21, 4411.
69. Ferreira MSV, Mousavi SH : Nanofiber technology in the ex vivo expansion of cord blood-derived hematopoietic stem cells. Nanomedicine 2018; 14: 1707-1718.
70. Mousavi SH, Abroun S, Soleimani M, Mowla SJ : 3-Dimensional nano-fibre scaffold for ex vivo expansion of cord blood haematopoietic stem cells. Artif Cells Nanomed Biotechnol 2018; 46: 740-748.
71. Kang YG, Shin JW, Park SH, Kim YM, Gu SR: A three-dimensional hierarchical scaffold fabricated by a combined rapid prototyping technique and electrospinning process to expand hematopoietic stem/progenitor cells. Biotechnol Lett 2016; 38: 175-181.
72. Ferreira MSV, Jahnen-Dechent W, Labude N, Bovi M, Hieronymus T: Cord blood-hematopoietic stem cell expansion in 3D fibrin scaffolds with stromal support. Biomaterials 2012; 33: 6987-6997.
73. Ferreira MV, Labude N, Piroth D, Jahnen-Dechent W, Knüchel R: Compatibility of different polymers for cord blood-derived hematopoietic progenitor cells. J Mater Sci Mater Med 2012; 23: 109-116.
74. Batnyam O, Shimizu H, Saito K, Ishida T, Suye S: Biohybrid hematopoietic niche for expansion of hematopoietic stem/progenitor cells by using geometrically controlled fibrous layers. RSC Advances 2015; 5: 80357-80364.
75. Pan X, Sun Q, Zhang Y, Cai H, Gao Y: Biomimetic macroporous pcl scaffolds for ex vivo expansion of cord blood‐derived CD34+ cells with feeder cells support. Macromol Biosci 2017; 17: 1-12.
76. Ma K, Chan C K, Liao S: Electrospun nanofiber scaffolds for rapid and rich capture of bone marrow-derived hematopoietic stem cells. Biomaterials 2008; 29(13): 2096–2103.
77. Feng Q, Chai C, Jiang X S: Expansion of engrafting human hematopoietic stem/progenitor cells in three-dimensional scaffolds with surface-immobilized fibronectin. Journal of Biomedical Materials Research 2006; 78A(4): 781–791.
78. Joseph M, Das M, Kanji S, Lu J, Aggarwal R, et al. Retention of stemness and vasculogenic potential of human umbilical cord blood stem cells after repeated expansions on PES-nanofiber matrices. Biomaterials. 2014; 35: 8566-8575.
79. Kanji S, Das M, Joseph M: Nanofiber-expanded human CD34+ cells heal cutaneous wounds in streptozotocin-induced diabetic mice. Sci Rep 2019; 9, 8415.
80. Chua KN, Chai C, Lee PC, Ramakrishna S, Leong KW, Mao HQ: Functional nanofiber scaffolds with different spacers modulate adhesion and expansion of cryopreserved umbilical cord blood hematopoietic stem/progenitor cells. Exp Hematol. 2007; 35(5):771-81. doi: 10.1016/j.exphem.2007.02.002. PMID: 17577926; PMCID: PMC2376815.
81. Mousavi SH, Abroun S, Soleimani M, Mowla SJ: Potential of Polycaprolactone Nanofiber Scaffold for Ex Vivo Expansion of Cord Blood-Derived CD34+ Hematopoietic Stem Cells. Int J Stem Cell Res Ther 2019; 5:059.
82. Fatemeh S, Karim S, Ali A M, Naser A, Mahin N, & Nadia B: Evaluation of human cord blood CD34+ hematopoietic stem cell differentiation to megakaryocyte on aminated PES nanofiber scaffold compare to 2-D culture system, Artificial Cells, Nanomedicine, and Biotechnology 2016; 44:4, 1062-1068, DOI: 10.3109/21691401.2015.1011800
83. Jiang X, Christopherson GT, Mao HQ: The effect of nanofibre surface amine density and conjugate structure on the adhesion and proliferation of human haematopoietic progenitor cells. Interface Focus 2011; 1, 725–733.

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