Skip to main content

Advertisement

SpringerLink
Log in

Stem Cell Treatment After Cerebral Ischemia Regulates the Gene Expression of Apoptotic Molecules

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Evidence suggests that apoptosis contributes significantly to cell death after cerebral ischemia. Our recent studies that utilized human umbilical cord blood-derived mesenchymal stem cells (hUCBSCs) demonstrated the potential of hUCBSCs to inhibit neuronal apoptosis in a rat model of CNS injury. Therefore, we hypothesize that intravenous administration of hUCBSCs after focal cerebral ischemia would reduce brain damage by inhibiting apoptosis and downregulating the upregulated apoptotic pathway molecules. Male Sprague–Dawley rats were obtained and randomly assigned to various groups. After the animals reached a desired weight, they were subjected to a 2 h middle cerebral artery occlusion (MCAO) procedure followed by 7 days of reperfusion. The hUCBSCs were obtained, cultured, and intravenously injected (0.25 × 106 cells or 1 × 106 cells) via the tail vein to separate groups of animals 24 h post-MCAO procedure. We performed various techniques including PCR microarray, hematoxylin and eosin, and TUNEL staining in addition to immunoblot and immunofluorescence analysis in order to investigate the effect of our treatment on regulation of apoptosis after focal cerebral ischemia. Most of the apoptotic pathway molecules which were upregulated after focal cerebral ischemia were downregulated after hUCBSCs treatment. Further, the staining techniques revealed a prominent reduction in brain damage and the extent of apoptosis at even the lowest dose of hUCBSCs tested in the present study. In conclusion, our treatment with hUCBSCs after cerebral ischemia in the rodent reduces brain damage by inhibiting apoptosis and downregulating the apoptotic pathway molecules.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Turner RC, Dodson SC, Rosen CL, Huber JD (2013) The science of cerebral ischemia and the quest for neuroprotection: navigating past failure to future success. J Neurosurg 118:1072–1085

    Article  CAS  PubMed  Google Scholar 

  2. Banerjee S, Williamson D, Habib N, Gordon M, Chataway J (2011) Human stem cell therapy in ischaemic stroke: a review. Age Ageing 40:7–13

    Article  PubMed  Google Scholar 

  3. Sinden JD, Vishnubhatla I, Muir KW (2012) Prospects for stem cell-derived therapy in stroke. Prog Brain Res 201:119–167

    Article  PubMed  Google Scholar 

  4. Buhnemann C, Scholz A, Bernreuther C, Malik CY, Braun H, Schachner M et al (2006) Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. Brain 129:3238–3248

    Article  PubMed  Google Scholar 

  5. Hicks A, Jolkkonen J (2009) Challenges and possibilities of intravascular cell therapy in stroke. Acta Neurobiol Exp (Wars) 69:1–11

    Google Scholar 

  6. Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY (2010) A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28:1099–1106

    Article  PubMed  Google Scholar 

  7. Veeravalli KK, Dasari VR, Fassett D, Dinh DH, Rao JS (2011) Human umbilical cord blood derived mesenchymal stem cells upregulate myelin basic protein in shiverer mice. Stem Cells Dev 20:881–891

    Article  CAS  PubMed  Google Scholar 

  8. Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE et al (2001) Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32:2682–2688

    Article  CAS  PubMed  Google Scholar 

  9. Vendrame M, Cassady J, Newcomb J, Butler T, Pennypacker KR, Zigova T et al (2004) Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke 35:2390–2395

    Article  PubMed  Google Scholar 

  10. Chung DJ, Choi CB, Lee SH, Kang EH, Lee JH, Hwang SH et al (2009) Intraarterially delivered human umbilical cord blood-derived mesenchymal stem cells in canine cerebral ischemia. J Neurosci Res 87:3554–3567

    Article  CAS  PubMed  Google Scholar 

  11. Riegelsberger UM, Deten A, Posel C, Zille M, Kranz A, Boltze J et al (2011) Intravenous human umbilical cord blood transplantation for stroke: impact on infarct volume and caspase-3-dependent cell death in spontaneously hypertensive rats. Exp Neurol 227:218–223

    Article  PubMed  Google Scholar 

  12. Lim JY, Jeong CH, Jun JA, Kim SM, Ryu CH, Hou Y et al (2011) Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia. Stem Cell Res Ther 2:38

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Kim ES, Ahn SY, Im GH, Sung DK, Park YR, Choi SH et al (2012) Human umbilical cord blood-derived mesenchymal stem cell transplantation attenuates severe brain injury by permanent middle cerebral artery occlusion in newborn rats. Pediatr Res 72:277–284

    Article  CAS  PubMed  Google Scholar 

  14. Dasari VR, Veeravalli KK, Tsung AJ, Gondi CS, Gujrati M, Dinh DH et al (2009) Neuronal apoptosis is inhibited by cord blood stem cells after spinal cord injury. J Neurotrauma 26:2057–2069

    Article  PubMed  Google Scholar 

  15. Chelluboina B, Klopfenstein JD, Gujrati M, Rao JS, Veeravalli KK (2014) Temporal regulation of apoptotic and anti-apoptotic molecules after middle cerebral artery occlusion followed by reperfusion. Mol Neurobiol 49:50–65

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Broughton BR, Reutens DC, Sobey CG (2009) Apoptotic mechanisms after cerebral ischemia. Stroke 40:e331–e339

    Article  PubMed  Google Scholar 

  17. Yuan J (2009) Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis 14:469–477

    Article  PubMed Central  PubMed  Google Scholar 

  18. Akpan N, Serrano-Saiz E, Zacharia BE, Otten ML, Ducruet AF, Snipas SJ et al (2011) Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke. J Neurosci 31:8894–8904

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Dasari VR, Spomar DG, Gondi CS, Sloffer CA, Saving KL, Gujrati M et al (2007) Axonal demyelination by cord blood stem cells after spinal cord injury. J Neurotrauma 24:391–410

    Article  PubMed Central  PubMed  Google Scholar 

  20. Dasari VR, Spomar DG, Li L, Gujrati M, Rao JS, Dinh DH (2008) Umbilical cord blood stem cell mediated downregulation of Fas improves functional recovery of rats after spinal cord injury. Neurochem Res 33:134–149

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Veeravalli KK, Dasari VR, Tsung AJ, Dinh DH, Gujrati M, Fassett D et al (2009) Human umbilical cord blood stem cells upregulate matrix metalloproteinase-2 in rats after spinal cord injury. Neurobiol Dis 36:200–212

    Article  CAS  PubMed  Google Scholar 

  22. Loddick SA, MacKenzie A, Rothwell NJ (1996) An ICE inhibitor, z-VAD-DCB attenuates ischaemic brain damage in the rat. NeuroReport 7:1465–1468

    Article  CAS  PubMed  Google Scholar 

  23. Hara H, Friedlander RM, Gagliardini V, Ayata C, Fink K, Huang Z et al (1997) Inhibition of interleukin 1 beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci USA 94:2007–2012

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Endres M, Namura S, Shimizu-Sasamata M, Waeber C, Zhang L, Gomez-Isla T et al (1998) Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J Cereb Blood Flow Metab 18:238–247

    Article  CAS  PubMed  Google Scholar 

  25. Cheng Y, Deshmukh M, D’Costa A, Demaro JA, Gidday JM, Shah A et al (1998) Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury. J Clin Invest 101:1992–1999

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Krupinski J, Lopez E, Marti E, Ferrer I (2000) Expression of caspases and their substrates in the rat model of focal cerebral ischemia. Neurobiol Dis 7:332–342

    Article  CAS  PubMed  Google Scholar 

  27. Li H, Colbourne F, Sun P, Zhao Z, Buchan AM, Iadecola C (2000) Caspase inhibitors reduce neuronal injury after focal but not global cerebral ischemia in rats. Stroke 31:176–182

    Article  CAS  PubMed  Google Scholar 

  28. Salvesen GS, Dixit VM (1999) Caspase activation: the induced-proximity model. Proc Natl Acad Sci USA 96:10964–10967

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Thorburn A (2004) Death receptor-induced cell killing. Cell Signal 16:139–144

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Noorjehan Ali for technical assistance, Debbie McCollum for manuscript preparation, and Diana Meister for manuscript review.

Author information

Authors and Affiliations

  1. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA

    Bharath Chelluboina & Krishna Kumar Veeravalli

  2. Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL, USA

    Jeffrey D. Klopfenstein

  3. Department of Pathology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA

    David M. Pinson

  4. Department of Neurology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA

    David Z. Wang

  5. Comprehensive Stroke Center, Illinois Neurological Institute, Peoria, IL, USA

    Jeffrey D. Klopfenstein & David Z. Wang

Authors
  1. Bharath Chelluboina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey D. Klopfenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David M. Pinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Z. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Krishna Kumar Veeravalli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Krishna Kumar Veeravalli.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chelluboina, B., Klopfenstein, J.D., Pinson, D.M. et al. Stem Cell Treatment After Cerebral Ischemia Regulates the Gene Expression of Apoptotic Molecules. Neurochem Res 39, 1511–1521 (2014). https://doi.org/10.1007/s11064-014-1341-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-014-1341-z

Keywords

Search

Navigation