• Cell-free biological agents: new horizons in the treatment of premature newborns (literature review)
en To content Full text of article

Cell-free biological agents: new horizons in the treatment of premature newborns (literature review)

Modern Pediatrics. Ukraine. (2023). 8(136): 86-93. doi: 10.15574/SP.2023.136.86
Hladkykh F. V.1,2,3, Koshurba I. V.3,4, Chyzh M. O.2, Zhuchenko P. S.5, Koshurba Yu. V.4
1State of Organization ''Grigoriev Institute for Medical Radiology and Oncology of the National Academy of Medical Sciences of Ukraine'', Kharkiv
2V.N. Karazin National University, Kharkiv, Ukraine
3Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine, Kharkiv
4Communal non-profit enterprise ''Chernivtsi Regional Perinatal Center'', Ukraine
5National Pirogov Memorial Medical University, Vinnytsya, Ukraine

For citation: Hladkykh FV, Koshurba IV, Chyzh MO, Zhuchenko PS, Koshurba YuV. (2023). Cell-free biological agents: new horizons in the treatment of premature newborns (literature review). Modern Pediatrics. Ukraine. 8(136): 86-93. doi: 10.15574/SP.2023.136.86.
Article received: Oct 02, 2023. Accepted for publication: Dec 12, 2023.

Preterm birth, is a complex syndrome and remains a major global health problem. Taking into account the plasticity and regenerative potential of developing organs, nowadays the most promising therapeutic strategy is the use of mesenchymal stem cells (MSCs) and their derivatives.
Aim. To summarize current information about the therapeutic potential of cell-free biological agents in the treatment of diseases of premature newborns according to data from open
sources of information.
Publications have been selected, which covered information on the use of conditioned media and MSC exosomes in the treatment of diseases of premature newborns. In comparison to MSCs, the use of cell-free agents has advantages: the use of the secretome eliminates the risks potentially associated with the transplantation of living and proliferative cell populations, including immune compatibility, tumorigenicity, emboli formation, and transmission of infections; MSC-derived secretome can be evaluated for safety, dosage, and efficacy in a manner similar to conventional pharmaceutical agents; storage can be carried out without the use of potentially toxic cryopreservatives for a long period without losing the effectiveness of the product; the use of secretome from MSCs, such as conditioned MSC medium, is more economical and more practical for clinical use, as it avoids invasive cell collection procedures; mass production is possible using custom-made cell lines in controlled laboratory conditions, providing a convenient source of bioactive factors; the time and cost of expansion and maintenance cultured stem cells could be greatly reduced, and ready-made secretome therapies could be immediately available for the treatment of acute conditions; a biological product obtained for therapeutic use can be modified to have the desired cell-specific effects.
Conclusions. The treatment of premature newborns represents a unique clinical task, since their diseases involve dynamic physiological processes in immature, developing organs. The introduction into clinical use of cell-free biological agents is one of the most promising areas in the development of neonatology and will obviously change the paradigms in the treatment of a number of diseases of newborns, in particular bronchopulmonary dysplasia, hypoxic ischemic encephalopathy and necrotizing enterocolitis.
No conflict of interests was declared by the authors.
Keywords: mesenchymal stem cells, exosomes, conditioned media, newborns, prematurity, bronchopulmonary dysplasia, hypoxic-ischemic encephalopathy, necrotizing enterocolitis.

REFERENCES

1. Abman SH, Matthay MA. (2009, Dec 1). Mesenchymal stem cells for the prevention of bronchopulmonary dysplasia: delivering the secretome. Am J Respir Crit Care Med. 180(11): 1039-1041. https://doi.org/10.1164/rccm.200909-1330ED; PMid:19923401

2. Ai D, Shen J, Sun J, Zhu Z, Gao R, Du Y et al. (2022, Feb). Mesenchymal Stem Cell-Derived Extracellular Vesicles Suppress Hyperoxia-Induced Transdifferentiation of Rat Alveolar Type 2 Epithelial Cells. Stem Cells Dev. 31(3-4): 53-66. Epub 2022 Jan 19. https://doi.org/10.1089/scd.2021.0256; PMid:34913742

3. Archambault J, Moreira A, McDaniel D, Winter L, Sun L, Hornsby P. (2017). Therapeutic potential of mesenchymal stromal cells for hypoxic ischemic encephalopathy: a systematic review and meta-analysis of preclinical studies. PLoS One. 12(12): e0189895. https://doi.org/10.1371/journal.pone.0189895; PMid:29261798 PMCid:PMC5736208

4. Aridas JD, McDonald CA, Paton MC. (2016). Cord blood mononuclear cells prevent neuronal apoptosis in response to perinatal asphyxia in the newborn lamb. J Physiol. 594(05): 1421-1435. https://doi.org/10.1113/JP271104; PMid:26527561 PMCid:PMC4771799

5. Augustine S, Avey MT, Harrison B, Locke T, Ghannad M, Moher D, Thébaud B. (2017, Dec). Mesenchymal Stromal Cell Therapy in Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis of Preclinical Studies. Stem Cells Transl Med. 6(12): 2079-2093. Epub 2017 Oct 17. https://doi.org/10.1002/sctm.17-0126; PMid:29045045 PMCid:PMC5702524

6. Chevin M, Guiraut C, Sébire G. (2018). Effect of hypothermia on interleukin-1 receptor antagonist pharmacodynamics in inflammatory-sensitized hypoxic-ischemic encephalopathy of term newborns. J Neuroinflammation. 15(01): 214. https://doi.org/10.1186/s12974-018-1258-6; PMid:30060742 PMCid:PMC6066954

7. Benny M, Courchia B, Shrager S, Sharma M, Chen P, Duara J et al. (2022, Mar 17). Comparative Effects of Bone Marrow-derived Versus Umbilical Cord Tissue Mesenchymal Stem Cells in an Experimental Model of Bronchopulmonary Dysplasia. Stem Cells Transl Med. 11(2): 189-199. https://doi.org/10.1093/stcltm/szab011; PMid:35298658 PMCid:PMC8929420

8. Chaubey S, Thueson S, Ponnalagu D, Alam MA, Gheorghe CP, Aghai Z et al. (2018, Jun 26). Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6. Stem Cell Res Ther. 9(1): 173. https://doi.org/10.1186/s13287-018-0903-4; PMid:29941022 PMCid:PMC6019224

9. Cunningham CJ, Redondo-Castro E, Allan SM. (2018). The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J Cereb Blood Flow Metab. [Internet]. 38: 1276-1292. URL: http://www.ncbi.nlm.nih.gov/pubmed/29768965. https://doi.org/10.1177/0271678X18776802; PMid:29768965 PMCid:PMC6077926

10. Damianos A, Sammour I. (2023, Apr). Barriers in translating stem cell therapies for neonatal diseases. Semin Perinatol. 47(3): 151731. Epub 2023 Mar 16. https://doi.org/10.1016/j.semperi.2023.151731; PMid:36990922

11. Davidson JO, Wassink G, van den Heuij LG, Bennet L, Gunn AJ. (2015, Sep 14). Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy - Where to from Here? Front Neurol. 6: 198. https://doi.org/10.3389/fneur.2015.00198; PMid:26441818 PMCid:PMC4568393

12. Ding M, Shen Y, Wang P. (2018). Exosomes isolated from human umbilical cord mesenchymal stem cells alleviate neuroinflammation and reduce amyloid-beta deposition by modulating microglial activation in Alzheimer's disease. Neurochem Res. 43(11): 2165-2177. https://doi.org/10.1007/s11064-018-2641-5; PMid:30259257

13. Gu Y, Zhang Y, Bi Y, Liu J, Tan B, Gong M et al. (2015, Oct 17). Mesenchymal stem cells suppress neuronal apoptosis and decrease IL-10 release via the TLR2/NFκB pathway in rats with hypoxic-ischemic brain damage. Mol Brain. 8(1): 65. https://doi.org/10.1186/s13041-015-0157-3; PMid:26475712 PMCid:PMC4609057

14. Guo Z Y, Sun X, Xu X L, Zhao Q, Peng J, Wang Y. (2015). Human umbilical cord mesenchymal stem cells promote peripheral nerve repair via paracrine mechanisms. Neural Regen Res. 10(04): 651-658. https://doi.org/10.4103/1673-5374.155442; PMid:26170829 PMCid:PMC4424761

15. Harrell CR, Fellabaum C, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. (2019, May 16). Molecular Mechanisms Responsible for Therapeutic Potential of Mesenchymal Stem Cell-Derived Secretome. Cells. 8(5): 467. https://doi.org/10.3390/cells8050467; PMid:31100966 PMCid:PMC6562906

16. Hattori T, Sato Y, Kondo T. (2015). Administration of umbilical cord blood cells transiently decreased hypoxic-ischemic brain injury in neonatal rats. Dev Neurosci. 37(02): 95-104. https://doi.org/10.1159/000368396; PMid:25720519

17. Hladkykh FV. (2021). The effect of meloxicam and cryopreserved placenta extract on initial inflammatory response (an experimental study). Ceska a Slovenska Farmacie. 70 (5): 179-185. https://doi.org/10.5817/CSF2021-5-179

18. Hladkykh FV. (2021). Anti-inflammatory properties of diclofenac sodium on background of its combined use with cryopreserved placenta extract in experiment. Problems of Cryobiology and Cryomedicine. 31 (4): 364-367. https://doi.org/10.15407/cryo31.04.364

19. Hladkykh FV, Chyzh MO, Manchenko AO, Belochkіna IV, Mikhailova IP. (2021). Effect of cryopreserved placenta extract on some biochemical indices of therapeutic efficiency and toxicity of diclofenac sodium in adjuvant-induced experimental arthritis. Pharmacy & Pharmacology. 9 (4): 278-293. https://doi.org/10.19163/2307-9266-2021-9-4-278-293

20. Kikuchi-Taura A, Okinaka Y, Takeuchi Y. (2020). Bone marrow mononuclear cells activate angiogenesis via GAP junction-mediated cell-cell interaction. Stroke. 51(04): 1279-1289. https://doi.org/10.1161/STROKEAHA.119.028072; PMid:32075549

21.Kim S, Kim Y E, Hong S. (2020). Reactive microglia and astrocytes in neonatal intraventricular hemorrhage model are blocked by mesenchymal stem cells. Glia. 68(01): 178-192. https://doi.org/10.1002/glia.23712; PMid:31441125

22. Koshurba IV, Chyzh MO, Hladkykh FV. (2022). Influence of placenta cryoextract on the liver metabolic and functional state in case of D-galactosamine hepatitis. Innovative Biosystems and Bioengineering. 6 (2): 64-74. https://doi.org/10.20535/ibb.2022.6.2.264774

23. Koshurba IV, Hladkykh FV, Chyzh MO, Belochkina IV, Rubleva TV. (2022). Hepatotropic effects of triple antiulcer therapy and placenta cryoextract: the role of sex factors in lipoperoxidation. Fiziolohichnyi zhurnal. 68 (5): 25-32. https://doi.org/10.15407/fz68.05.025

24. Kourembanas S. (2015). Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol. 77:13-27. Epub 2014 Sep 25. https://doi.org/10.1146/annurev-physiol-021014-071641; PMid:25293529

25. Li B, Hock A, Wu RY et al. (2019). Bovine milk-derived exosomes enhance goblet cell activity and prevent the development of experimental necrotizing enterocolitis. PLoS One. [Internet]. 14: e0211431. URL: http://dx.plos.org/10.1371/journal.pone.0211431. https://doi.org/10.1371/journal.pone.0211431; PMid:30699187 PMCid:PMC6353182

26. Li J, Yawno T, Sutherland A. (2016). Preterm white matter brain injury is prevented by early administration of umbilical cord blood cells. Exp Neurol. 283; pt A: 179-187. https://doi.org/10.1016/j.expneurol.2016.06.017; PMid:27317990

27. Lingappan K, Savani RC. (2020, May 15). The Wnt Signaling Pathway and the Development of Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 201(10): 1174-1176. https://doi.org/10.1164/rccm.202002-0277ED; PMid:32101467 PMCid:PMC7233338

28. Maldonado VV, Patel NH, Smith EE, Barnes CL, Gustafson MP, Rao RR, Samsonraj RM. (2023, Jul 11). Clinical utility of mesenchymal stem/stromal cells in regenerative medicine and cellular therapy. J Biol Eng. 17(1): 44. https://doi.org/10.1186/s13036-023-00361-9; PMid:37434264 PMCid:PMC10334654

29. Marolt Presen D, Traweger A, Gimona M, Redl H. (2019, Nov 27). Mesenchymal Stromal Cell-Based Bone Regeneration Therapies: From Cell Transplantation and Tissue Engineering to Therapeutic Secretomes and Extracellular Vesicles. Front Bioeng Biotechnol. 7: 352. https://doi.org/10.3389/fbioe.2019.00352; PMid:31828066 PMCid:PMC6890555

30. McCulloh CJ, Olson JK, Wang Y et al. (2018). Treatment of experimental necrotizing enterocolitis with stem cell-derived exosomes. J Pediatr Surg. [Internet]. 53: 1215-1220. URL: http://www.ncbi.nlm.nih.gov/pubmed/29661576. https://doi.org/10.1016/j.jpedsurg.2018.02.086; PMid:29661576 PMCid:PMC5994352

31. McCulloh CJ, Olson JK, Zhou Y, Wang Y, Besner GE. (2017). Stem cells and necrotizing enterocolitis: A direct comparison of the efficacy of multiple types of stem cells. J Pediatr Surg. [Internet]. 52: 999-1005. URL: https://linkinghub.elsevier.com/retrieve/pii/S002234681730177X. https://doi.org/10.1016/j.jpedsurg.2017.03.028; PMid:28366560 PMCid:PMC5467690

32. McManus T, Sadgrove M, Pringle AK, Chad JE, Sundstrom LE. (2004). Intraischaemic hypothermia reduces free radical production and protects against ischaemic insults in cultured hippocampal slices. J Neurochem. 91(02): 327-336. https://doi.org/10.1111/j.1471-4159.2004.02711.x; PMid:15447666

33. Mukai T, Martino E D, Tsuji S. (2021). Umbilical cord tissue-derived mesenchymal stromal cells immunomodulate and restore actin dynamics and phagocytosis of lipopolysaccharide-activated microglia via the PI3K/Akt/Rho GTPase pathway, with lot-to-lot variation. Cell Death Disc. 7: 46. https://doi.org/10.1038/s41420-021-00436-w; PMid:33723246 PMCid:PMC7961004

34. Mukai T, Tojo A, Nagamura-Inoue T. (2018). Umbilical cord-derived mesenchymal stromal cells contribute to neuroprotection in neonatal cortical neurons damaged by oxygen-glucose deprivation. Front Neurol. 9: 466. https://doi.org/10.3389/fneur.2018.00466; PMid:29963009 PMCid:PMC6013549

35. Nabetani M, Mukai T, Shintaku H. (2022, Dec). Preventing Brain Damage from Hypoxic-Ischemic Encephalopathy in Neonates: Update on Mesenchymal Stromal Cells and Umbilical Cord Blood Cells. Am J Perinatol. 39(16): 1754-1763. Epub 2021 Apr 14. https://doi.org/10.1055/s-0041-1726451; PMid:33853147 PMCid:PMC9674406

36. Nagamura-Inoue T, Mukai T. (2016). Umbilical cord is a rich source of mesenchymal stromal cells for cell therapy. Curr Stem Cell Res Ther. 11(08): 634-642. https://doi.org/10.2174/1574888X10666151026115017; PMid:26496885

37. Nguyen LT, Trieu TTH, Bui HTH, Hoang VT, Nguyen ATT, Trinh NTH et al. (2020, Oct 20). Allogeneic administration of human umbilical cord-derived mesenchymal stem/stromal cells for bronchopulmonary dysplasia: preliminary outcomes in four Vietnamese infants. J Transl Med. 18(1): 398. https://doi.org/10.1186/s12967-020-02568-6; PMid:33081796 PMCid:PMC7576694

38. Nitkin CR, Rajasingh J, Pisano C, Besner GE, Thébaud B, Sampath V. (2020, Jan). Stem cell therapy for preventing neonatal diseases in the 21st century: Current understanding and challenges. Pediatr Res. 87(2): 265-276. Epub 2019 May 14. https://doi.org/10.1038/s41390-019-0425-5; PMid:31086355 PMCid:PMC6854309

39. Northway WH. (1970, May). Perinatal pulmonary roentgenography. Calif Med. 112(5): 59-60. PMID: 18730313; PMCID: PMC1501241.

40. Perrone S, Weiss M D, Proietti F. (2018). Identification of a panel of cytokines in neonates with hypoxic ischemic encephalopathy treated with hypothermia. Cytokine. 111: 119-124. https://doi.org/10.1016/j.cyto.2018.08.011; PMid:30142532

41. Phan J, Kumar P, Hao D, Gao K, Farmer D, Wang A. (2018, Sep 26). Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell-free therapy. J Extracell Vesicles. 7(1): 1522236. https://doi.org/10.1080/20013078.2018.1522236; PMid:30275938 PMCid:PMC6161586

42. Pogozhykh O, Prokopyuk V, Figueiredo C, Pogozhykh D. (2018, Jan 18). Placenta and Placental Derivatives in Regenerative Therapies: Experimental Studies, History, and Prospects. Stem Cells Int. 2018: 4837930. https://doi.org/10.1155/2018/4837930; PMid:29535770 PMCid:PMC5822788

43. Porzionato A, Zaramella P, Dedja A, Guidolin D, Van Wemmel K, Macchi V et al. (2019, Jan 1). Intratracheal administration of clinical-grade mesenchymal stem cell-derived extracellular vesicles reduces lung injury in a rat model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 316(1): L6-L19. Epub 2018 Oct 4. https://doi.org/10.1152/ajplung.00109.2018; PMid:30284924

44. Rocha-Ferreira E, Vincent A, Bright S, Peebles D M, Hristova M. (2018). The duration of hypothermia affects short-term neuroprotection in a mouse model of neonatal hypoxic ischaemic injury. PLoS One. 13(07): e0199890. https://doi.org/10.1371/journal.pone.0199890; PMid:29969470 PMCid:PMC6029790

45. Rosenkranz K, Kumbruch S, Lebermann K. (2010). The chemokine SDF-1/CXCL12 contributes to the 'homing' of umbilical cord blood cells to a hypoxic-ischemic lesion in the rat brain. J Neurosci Res. 88(06): 1223-1233. https://doi.org/10.1002/jnr.22292; PMid:19937807

46. Sammour I, Somashekar S, Huang J, Batlahally S, Breton M, Valasaki K et al. (2016, Oct 6). The Effect of Gender on Mesenchymal Stem Cell (MSC) Efficacy in Neonatal Hyperoxia-Induced Lung Injury. PLoS One. 11(10): e0164269. https://doi.org/10.1371/journal.pone.0164269; PMid:27711256 PMCid:PMC5053475

47. Serrenho I, Rosado M, Dinis A, Cardoso MC, Grãos M, Manadas B, Baltazar G. (2021, Mar 19). Stem Cell Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Systematic Review of Preclinical Studies. Int J Mol Sci. 22(6): 3142. https://doi.org/10.3390/ijms22063142; PMid:33808671 PMCid:PMC8003344

48. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S et al. (2015, Sep 8). Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012. JAMA. 314(10): 1039-1051. https://doi.org/10.1001/jama.2015.10244; PMid:26348753 PMCid:PMC4787615

49. Stoorvogel W. (2012). Functional transfer of microRNA by exosomes. Blood. [Internet]. 119: 646-648. URL: http://www.ncbi.nlm.nih.gov/pubmed/22262. https://doi.org/10.1182/blood-2011-11-389478; PMid:22262739

50. Sutsko RP, Young KC, Ribeiro A, Torres E, Rodriguez M, Hehre D et al. (2013, Jan). Long-term reparative effects of mesenchymal stem cell therapy following neonatal hyperoxia-induced lung injury. Pediatr Res. 73(1): 46-53. Epub 2012 Nov 8. https://doi.org/10.1038/pr.2012.152; PMid:23138401

51. Van Velthoven CT, Kavelaars A, Heijnen CJ. (2012, Apr). Mesenchymal stem cells as a treatment for neonatal ischemic brain damage. Pediatr Res. 71 (4 Pt 2): 474-481. Epub 2012 Feb 8. https://doi.org/10.1038/pr.2011.64; PMid:22430383

52. Villatoro AJ, Alcoholado C, Martín-Astorga MC, Fernández V, Cifuentes M, Becerra J. (2019, Feb). Comparative analysis and characterization of soluble factors and exosomes from cultured adipose tissue and bone marrow mesenchymal stem cells in canine species. Vet Immunol Immunopathol. 208: 6-15. Epub 2018 Dec 18. https://doi.org/10.1016/j.vetimm.2018.12.003; PMid:30712794

53. Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. (2017, Aug 25). Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int J Mol Sci. 18(9): 1852. https://doi.org/10.3390/ijms18091852; PMid:28841158 PMCid:PMC5618501

54. Wang Y, Long W, Cao Y, Li J, You L, Fan Y. (2020, May 29). Mesenchymal stem cell-derived secretomes for therapeutic potential of premature infant diseases. Biosci Rep. 40(5): BSR20200241. https://doi.org/10.1042/BSR20200241; PMid:32320046 PMCid:PMC7953482

55. Willis GR, Mitsialis SA, Kourembanas S. (2018, Jan). "Good things come in small packages": application of exosome-based therapeutics in neonatal lung injury. Pediatr Res. 83(1-2): 298-307. Epub 2017 Nov 22. https://doi.org/10.1038/pr.2017.256; PMid:28985201 PMCid:PMC5876073

56. Wu X, Xia Y, Zhou O, Song Y, Zhang X, Tian D et al. (2020, Jan 31). Allogeneic human umbilical cord-derived mesenchymal stem cells for severe bronchopulmonary dysplasia in children: study protocol for a randomized controlled trial (MSC-BPD trial). Trials. 21(1): 125. https://doi.org/10.1186/s13063-019-3935-x; PMid:32005282 PMCid:PMC6995070

57. Wu Y, Li J, Yuan R, Deng Z, Wu X. (2021, Jan 15). Bone marrow mesenchymal stem cell-derived exosomes alleviate hyperoxia-induced lung injury via the manipulation of microRNA-425. Arch Biochem Biophys. 697: 108712. Epub 2020 Nov 29. https://doi.org/10.1016/j.abb.2020.108712; PMid:33264631

58. Xi Y, Ju R, Wang Y. (2022, Apr 4). Mesenchymal Stem Cell-Derived Extracellular Vesicles for the Treatment of Bronchopulmonary Dysplasia. Front Pediatr. 10: 852034. https://doi.org/10.3389/fped.2022.852034; PMid:35444971 PMCid:PMC9013803

59. You J, Zhou O, Liu J, Zou W, Zhang L, Tian D et al. (2020, Dec 1). Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Alleviate Lung Injury in Rat Model of Bronchopulmonary Dysplasia by Affecting Cell Survival and Angiogenesis. Stem Cells Dev. 29(23): 1520-1532. Epub 2020 Nov 4. https://doi.org/10.1089/scd.2020.0156; PMid:33040709

60. Zhou T, Lin H, Jiang L. (2018). Mild hypothermia protects hippocampal neurons from oxygen-glucose deprivation injury through inhibiting caspase-3 activation. Cryobiology. 80: 55-61. https://doi.org/10.1016/j.cryobiol.2017.12.004; PMid:29223591