The Action of Hematopoietic Stem Cells in the Pathophysiological Mechanisms of Spinal Cord Injury
Keywords:
“spinal cord injury”, “hematopoietic stem cells”, “transplantation”Abstract
Spinal cord injury (SCI) often leads to catastrophic neurological deficits that dramatically reduce a person’s quality of life. Stem cells have attracted particular interest as a potential source for cell regeneration therapy after SCI.
The purpose of this study is to review the action of hematopoietic stem cells (HSCs) in the pathophysiological mechanisms of SCI. A literature review was conducted based on the Pubmed internet database, following the PRISMA Guidelines. Article titles were searched with the use of the keywords: (“hematopoietic stem cells” OR “HSCs”) AND (“spinal cord injury”). The search included only animal and clinical studies evaluating the action of hematopoietic stem cells in the pathophysiological mechanisms of SCI. Studies published in non-English language, reviews, case reports and study protocols were excluded.
Initially, 39 studies were identified after primary search on Pubmed electronic database. After screening of titles and abstracts, 21 articles were excluded. Among the remaining 18 studies, 9 were rejected as review articles. After checking the references list of the included studies, 13 more studies were added, leaving 22 studies for final analysis. There were 10 clinical studies and 12 animal studies.
The transplanted HSCs may integrate with the host cells in the injured spinal cord tissue, modulating immune and inflammatory reactions. Moreover, they have been associated with axon regeneration and remyelination along with a reduction of glial scar. HSC transplantation has shown promising results in the treatment of SCI, having the potential to repair the injured spinal cord and to enhance functional recovery. However, most studies are experimental and further human studies are needed to fully elucidate the role of HSC in SCI.
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References
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4. Fuchs E, Segre JA. Stem cells: a new lease on life. Cell. 2000 Jan 7;100(1):143-55.
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6. Barriga F, Ramírez P, Wietstruck A, Rojas N. Hematopoietic stem cell transplantation: clinical use and perspectives. Biol Res. 2012;45(3):307-16.
7. Jansen J, Hanks S, Thompson JM, Dugan MJ, Akard LP. Transplantation of hematopoietic stem cells from the peripheral blood. J Cell Mol Med. 2005 Jan-Mar;9(1):37-50.
8. Pei X. Who is hematopoietic stem cell: CD34+ or CD34-? Int J Hematol. 1999 Dec;70(4):213-5.
9. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9194-9.
10. Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W. Cell transplantation therapy for spinal cord injury. Nat Neurosci. 2017 Apr 25;20(5):637-47.
11. Martin-Lopez M, Fernandez-Muñoz B, Canovas S. Pluripotent Stem Cells for Spinal Cord Injury Repair. Cells. 2021 Nov 27;10(12).
12. Barnett I, Malik N, Kuijjer ML, Mucha PJ, Onnela JP. EndNote: Feature-based classification of networks. Netw Sci (Camb Univ Press). 2019 Sep;7(3):438-44.
13. Ammar AS, Osman Y, Hendam AT, Hasen MA, Al Rubaish FA, Al Nujaidi DY, et al. A Method for Reconstruction of Severely Damaged Spinal Cord using Autologous Hematopoietic Stem Cells and Platelet-rich Protein as a Biological Scaffold. Asian J Neurosurg. 2017 Oct-Dec;12(4):681-90.
14. Bryukhovetskiy AS, Bryukhovetskiy IS. Effectiveness of repeated transplantations of hematopoietic stem cells in spinal cord injury. World J Transplant. 2015 Sep 24;5(3):110-28.
15. Deda H, Inci MC, Kürekçi AE, Kayihan K, Ozgün E, Ustünsoy GE, et al. Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year follow-up. Cytotherapy. 2008;10(6):565-74.
16. Frolov AA, Bryukhovetskiy AS. Effects of hematopoietic autologous stem cell transplantation to the chronically injured human spinal cord evaluated by motor and somatosensory evoked potentials methods. Cell Transplant. 2012;21 Suppl 1:S49-55.
17. Hammadi AA, Marino A, Farhan S. Clinical response of 277 patients with spinal cord injury to stem cell therapy in iraq. Int J Stem Cells. 2012 May;5(1):76-8.
18. Thakkar UG, Vanikar AV, Trivedi HL, Shah VR, Dave SD, Dixit SB, et al. Infusion of autologous adipose tissue derived neuronal differentiated mesenchymal stem cells and hematopoietic stem cells in post-traumatic paraplegia offers a viable therapeutic approach. Adv Biomed Res. 2016;5:51.
19. Al-Zoubi A, Jafar E, Jamous M, Al-Twal F, Al-Bakheet S, Zalloum M, et al. Transplantation of purified autologous leukapheresis-derived CD34+ and CD133+ stem cells for patients with chronic spinal cord injuries: long-term evaluation of safety and efficacy. Cell Transplant. 2014;23 Suppl 1:S25-34.
20. Geffner LF, Santacruz P, Izurieta M, Flor L, Maldonado B, Auad AH, et al. Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplant. 2008;17(12):1277-93.
21. Cristante AF, Barros-Filho TE, Tatsui N, Mendrone A, Caldas JG, Camargo A, et al. Stem cells in the treatment of chronic spinal cord injury: evaluation of somatosensitive evoked potentials in 39 patients. Spinal Cord. 2009 Oct;47(10):733-8.
22. Callera F, de Melo CM. Magnetic resonance tracking of magnetically labeled autologous bone marrow CD34+ cells transplanted into the spinal cord via lumbar puncture technique in patients with chronic spinal cord injury: CD34+ cells’ migration into the injured site. Stem Cells Dev. 2007 Jun;16(3):461-6.
23. Koda M, Okada S, Nakayama T, Koshizuka S, Kamada T, Nishio Y, et al. Hematopoietic stem cell and marrow stromal cell for spinal cord injury in mice. Neuroreport. 2005 Nov 7;16(16):1763-7.
24. Koshizuka S, Okada S, Okawa A, Koda M, Murasawa M, Hashimoto M, et al. Transplanted hematopoietic stem cells from bone marrow differentiate into neural lineage cells and promote functional recovery after spinal cord injury in mice. J Neuropathol Exp Neurol. 2004 Jan;63(1):64-72.
25. Xiong LL, Liu F, Deng SK, Liu J, Dan QQ, Zhang P, et al. Transplantation of Hematopoietic Stem Cells Promotes Functional Improvement Associated with NT-3-MEK-1 Activation in Spinal Cord-Transected Rats. Front Cell Neurosci. 2017;11:213.
26. Nishio Y, Koda M, Kamada T, Someya Y, Yoshinaga K, Okada S, et al. The use of hemopoietic stem cells derived from human umbilical cord blood to promote restoration of spinal cord tissue and recovery of hindlimb function in adult rats. Journal of Neurosurgery: Spine SPI. 2006 01 Nov. 2006;5(5):424-33.
27. Yeng CH, Chen PJ, Chang HK, Lo WY, Wu CC, Chang CY, et al. Attenuating spinal cord injury by conditioned medium from human umbilical cord blood-derived CD34⁺ cells in rats. Taiwan J Obstet Gynecol. 2016 Feb;55(1):85-93.
28. Zhao ZM, Li HJ, Liu HY, Lu SH, Yang RC, Zhang QJ, et al. Intraspinal transplantation of CD34+ human umbilical cord blood cells after spinal cord hemisection injury improves functional recovery in adult rats. Cell Transplant. 2004;13(2):113-22.
29. Kao CH, Chen SH, Chio CC, Lin MT. Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and neurotrophic factors. Shock. 2008 Jan;29(1):49-55.
30. Ning G, Tang L, Wu Q, Li Y, Zhang C, Feng S. Human umbilical cord blood stem cells for spinal cord injury: early transplantation results in better local angiogenesis. Regen Med. 2013 May;8(3):271-81.
31. Judas GI, Ferreira SG, Simas R, Sannomiya P, Benício A, da Silva LF, et al. Intrathecal injection of human umbilical cord blood stem cells attenuates spinal cord ischaemic compromise in rats. Interact Cardiovasc Thorac Surg. 2014 Jun;18(6):757-62.
32. Dasari VR, Spomar DG, Gondi CS, Sloffer CA, Saving KL, Gujrati M, et al. Axonal remyelination by cord blood stem cells after spinal cord injury. J Neurotrauma. 2007 Feb;24(2):391-410.
33. Dasari VR, Veeravalli KK, Tsung AJ, Gondi CS, Gujrati M, Dinh DH, et al. Neuronal apoptosis is inhibited by cord blood stem cells after spinal cord injury. J Neurotrauma. 2009 Nov;26(11):2057-69.
34. Takahashi H, Koda M, Hashimoto M, Furuya T, Sakuma T, Kato K, et al. Transplanted Peripheral Blood Stem Cells Mobilized by Granulocyte Colony-Stimulating Factor Promoted Hindlimb Functional Recovery After Spinal Cord Injury in Mice. Cell Transplant. 2016;25(2):283-92.
35. Takakura N, Watanabe T, Suenobu S, Yamada Y, Noda T, Ito Y, et al. A role for hematopoietic stem cells in promoting angiogenesis. Cell. 2000 Jul 21;102(2):199-209.
36. Valable S, Bellail A, Lesné S, Liot G, Mackenzie ET, Vivien D, et al. Angiopoietin-1-induced PI3-kinase activation prevents neuronal apoptosis. FASEB J. 2003 Mar;17(3):443-5.
37. Park DH, Lee JH, Borlongan CV, Sanberg PR, Chung YG, Cho TH. Transplantation of umbilical cord blood stem cells for treating spinal cord injury. Stem Cell Rev Rep. 2011 Mar;7(1):181-94.
38. Ogawa Y, Sawamoto K, Miyata T, Miyao S, Watanabe M, Nakamura M, et al. Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res. 2002 Sep 15;69(6):925-33.
39. Nakamura M, Houghtling RA, MacArthur L, Bayer BM, Bregman BS. Differences in cytokine gene expression profile between acute and secondary injury in adult rat spinal cord. Exp Neurol. 2003 Nov;184(1):313-25.
40. Newman MB, Davis CD, Borlongan CV, Emerich D, Sanberg PR. Transplantation of human umbilical cord blood cells in the repair of CNS diseases. Expert Opin Biol Ther. 2004 Feb;4(2):121-30.
2. Karsy M, Hawryluk G. Modern Medical Management of Spinal Cord Injury. Curr Neurol Neurosci Rep. 2019 Jul 30;19(9):65.
3. Alizadeh A, Dyck SM, Karimi-Abdolrezaee S. Traumatic Spinal Cord Injury: An Overview of Pathophysiology, Models and Acute Injury Mechanisms. Front Neurol. 2019;10:282.
4. Fuchs E, Segre JA. Stem cells: a new lease on life. Cell. 2000 Jan 7;100(1):143-55.
5. Mikkola HK, Orkin SH. The journey of developing hematopoietic stem cells. Development. 2006 Oct;133(19):3733-44.
6. Barriga F, Ramírez P, Wietstruck A, Rojas N. Hematopoietic stem cell transplantation: clinical use and perspectives. Biol Res. 2012;45(3):307-16.
7. Jansen J, Hanks S, Thompson JM, Dugan MJ, Akard LP. Transplantation of hematopoietic stem cells from the peripheral blood. J Cell Mol Med. 2005 Jan-Mar;9(1):37-50.
8. Pei X. Who is hematopoietic stem cell: CD34+ or CD34-? Int J Hematol. 1999 Dec;70(4):213-5.
9. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9194-9.
10. Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W. Cell transplantation therapy for spinal cord injury. Nat Neurosci. 2017 Apr 25;20(5):637-47.
11. Martin-Lopez M, Fernandez-Muñoz B, Canovas S. Pluripotent Stem Cells for Spinal Cord Injury Repair. Cells. 2021 Nov 27;10(12).
12. Barnett I, Malik N, Kuijjer ML, Mucha PJ, Onnela JP. EndNote: Feature-based classification of networks. Netw Sci (Camb Univ Press). 2019 Sep;7(3):438-44.
13. Ammar AS, Osman Y, Hendam AT, Hasen MA, Al Rubaish FA, Al Nujaidi DY, et al. A Method for Reconstruction of Severely Damaged Spinal Cord using Autologous Hematopoietic Stem Cells and Platelet-rich Protein as a Biological Scaffold. Asian J Neurosurg. 2017 Oct-Dec;12(4):681-90.
14. Bryukhovetskiy AS, Bryukhovetskiy IS. Effectiveness of repeated transplantations of hematopoietic stem cells in spinal cord injury. World J Transplant. 2015 Sep 24;5(3):110-28.
15. Deda H, Inci MC, Kürekçi AE, Kayihan K, Ozgün E, Ustünsoy GE, et al. Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year follow-up. Cytotherapy. 2008;10(6):565-74.
16. Frolov AA, Bryukhovetskiy AS. Effects of hematopoietic autologous stem cell transplantation to the chronically injured human spinal cord evaluated by motor and somatosensory evoked potentials methods. Cell Transplant. 2012;21 Suppl 1:S49-55.
17. Hammadi AA, Marino A, Farhan S. Clinical response of 277 patients with spinal cord injury to stem cell therapy in iraq. Int J Stem Cells. 2012 May;5(1):76-8.
18. Thakkar UG, Vanikar AV, Trivedi HL, Shah VR, Dave SD, Dixit SB, et al. Infusion of autologous adipose tissue derived neuronal differentiated mesenchymal stem cells and hematopoietic stem cells in post-traumatic paraplegia offers a viable therapeutic approach. Adv Biomed Res. 2016;5:51.
19. Al-Zoubi A, Jafar E, Jamous M, Al-Twal F, Al-Bakheet S, Zalloum M, et al. Transplantation of purified autologous leukapheresis-derived CD34+ and CD133+ stem cells for patients with chronic spinal cord injuries: long-term evaluation of safety and efficacy. Cell Transplant. 2014;23 Suppl 1:S25-34.
20. Geffner LF, Santacruz P, Izurieta M, Flor L, Maldonado B, Auad AH, et al. Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplant. 2008;17(12):1277-93.
21. Cristante AF, Barros-Filho TE, Tatsui N, Mendrone A, Caldas JG, Camargo A, et al. Stem cells in the treatment of chronic spinal cord injury: evaluation of somatosensitive evoked potentials in 39 patients. Spinal Cord. 2009 Oct;47(10):733-8.
22. Callera F, de Melo CM. Magnetic resonance tracking of magnetically labeled autologous bone marrow CD34+ cells transplanted into the spinal cord via lumbar puncture technique in patients with chronic spinal cord injury: CD34+ cells’ migration into the injured site. Stem Cells Dev. 2007 Jun;16(3):461-6.
23. Koda M, Okada S, Nakayama T, Koshizuka S, Kamada T, Nishio Y, et al. Hematopoietic stem cell and marrow stromal cell for spinal cord injury in mice. Neuroreport. 2005 Nov 7;16(16):1763-7.
24. Koshizuka S, Okada S, Okawa A, Koda M, Murasawa M, Hashimoto M, et al. Transplanted hematopoietic stem cells from bone marrow differentiate into neural lineage cells and promote functional recovery after spinal cord injury in mice. J Neuropathol Exp Neurol. 2004 Jan;63(1):64-72.
25. Xiong LL, Liu F, Deng SK, Liu J, Dan QQ, Zhang P, et al. Transplantation of Hematopoietic Stem Cells Promotes Functional Improvement Associated with NT-3-MEK-1 Activation in Spinal Cord-Transected Rats. Front Cell Neurosci. 2017;11:213.
26. Nishio Y, Koda M, Kamada T, Someya Y, Yoshinaga K, Okada S, et al. The use of hemopoietic stem cells derived from human umbilical cord blood to promote restoration of spinal cord tissue and recovery of hindlimb function in adult rats. Journal of Neurosurgery: Spine SPI. 2006 01 Nov. 2006;5(5):424-33.
27. Yeng CH, Chen PJ, Chang HK, Lo WY, Wu CC, Chang CY, et al. Attenuating spinal cord injury by conditioned medium from human umbilical cord blood-derived CD34⁺ cells in rats. Taiwan J Obstet Gynecol. 2016 Feb;55(1):85-93.
28. Zhao ZM, Li HJ, Liu HY, Lu SH, Yang RC, Zhang QJ, et al. Intraspinal transplantation of CD34+ human umbilical cord blood cells after spinal cord hemisection injury improves functional recovery in adult rats. Cell Transplant. 2004;13(2):113-22.
29. Kao CH, Chen SH, Chio CC, Lin MT. Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and neurotrophic factors. Shock. 2008 Jan;29(1):49-55.
30. Ning G, Tang L, Wu Q, Li Y, Zhang C, Feng S. Human umbilical cord blood stem cells for spinal cord injury: early transplantation results in better local angiogenesis. Regen Med. 2013 May;8(3):271-81.
31. Judas GI, Ferreira SG, Simas R, Sannomiya P, Benício A, da Silva LF, et al. Intrathecal injection of human umbilical cord blood stem cells attenuates spinal cord ischaemic compromise in rats. Interact Cardiovasc Thorac Surg. 2014 Jun;18(6):757-62.
32. Dasari VR, Spomar DG, Gondi CS, Sloffer CA, Saving KL, Gujrati M, et al. Axonal remyelination by cord blood stem cells after spinal cord injury. J Neurotrauma. 2007 Feb;24(2):391-410.
33. Dasari VR, Veeravalli KK, Tsung AJ, Gondi CS, Gujrati M, Dinh DH, et al. Neuronal apoptosis is inhibited by cord blood stem cells after spinal cord injury. J Neurotrauma. 2009 Nov;26(11):2057-69.
34. Takahashi H, Koda M, Hashimoto M, Furuya T, Sakuma T, Kato K, et al. Transplanted Peripheral Blood Stem Cells Mobilized by Granulocyte Colony-Stimulating Factor Promoted Hindlimb Functional Recovery After Spinal Cord Injury in Mice. Cell Transplant. 2016;25(2):283-92.
35. Takakura N, Watanabe T, Suenobu S, Yamada Y, Noda T, Ito Y, et al. A role for hematopoietic stem cells in promoting angiogenesis. Cell. 2000 Jul 21;102(2):199-209.
36. Valable S, Bellail A, Lesné S, Liot G, Mackenzie ET, Vivien D, et al. Angiopoietin-1-induced PI3-kinase activation prevents neuronal apoptosis. FASEB J. 2003 Mar;17(3):443-5.
37. Park DH, Lee JH, Borlongan CV, Sanberg PR, Chung YG, Cho TH. Transplantation of umbilical cord blood stem cells for treating spinal cord injury. Stem Cell Rev Rep. 2011 Mar;7(1):181-94.
38. Ogawa Y, Sawamoto K, Miyata T, Miyao S, Watanabe M, Nakamura M, et al. Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res. 2002 Sep 15;69(6):925-33.
39. Nakamura M, Houghtling RA, MacArthur L, Bayer BM, Bregman BS. Differences in cytokine gene expression profile between acute and secondary injury in adult rat spinal cord. Exp Neurol. 2003 Nov;184(1):313-25.
40. Newman MB, Davis CD, Borlongan CV, Emerich D, Sanberg PR. Transplantation of human umbilical cord blood cells in the repair of CNS diseases. Expert Opin Biol Ther. 2004 Feb;4(2):121-30.
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