The Effect of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells in a Collagenase-Induced Intracerebral Hemorrhage Rat Model

다국어 초록 (Multilingual Abstract)

Intracerebral hemorrhage (ICH) is one of the devastating types of stroke. Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have potential benefits in recovery from brain damage following ICH. This study aimed to identify the beneficial effects of hUCB-MSCs and investigate whether they have anti-inflammatory effects on the ICH brain via neurotrophic factors or cytokines. hUCB-MSCs were transplanted into a collagenase-induced ICH rat model. At 2, 9, 16, and 30 days after ICH, rotarod and limb placement tests were performed to measure behavioral outcomes. ICH rats were sacrificed to evaluate the volume of lesion using H&E staining. Immunostaining was performed to investigate neurogenesis, angiogenesis, and anti-apoptosis at 4 weeks after transplantation. Inflammatory factors (TNF-α, COX-2, microglia, and neutrophils) were analyzed by immunofluorescence staining, RT-PCR, and Western blot at 3 days after transplantation. hUCB-MSCs were associated with neurological benefits and reduction in lesion volume. The hUCB-MSCs-treated group tended to reveal high levels of neurogenesis, angiogenesis, and anti-apoptosis (significant for angiogenesis). The expression levels of inflammatory factors tended to be reduced in the hUCB-MSCs-treated group compared with the controls. Our study suggests that hUCB-MSCs may improve neurological outcomes and modulate inflammation-associated immune cells and cytokines in ICH-induced inflammatory responses.

참고문헌 (Reference)

1 Lei B, "Tumor necrosis factor α antagonism improves neurological recovery in murine intracerebral hemorrhage" 10 : 103-, 2013

2 Dalous J, "Transplantation of umbilical cord-derived mesenchymal stem cells as a novel strategy to protect the central nervous system: technical aspects, preclinical studies, and clinical perspectives" 71 : 482-490, 2012

3 Jeong SY, "Thrombospondin-2 secreted by human umbilical cord blood-derived mesenchymal stem cells promotes chondrogenic differentiation" 31 : 2136-2148, 2013

4 Wang SP, "Therapeutic effect of mesenchymal stem cells in rats with intracerebral hemorrhage: reduced apoptosis and enhanced neuroprotection" 6 : 848-854, 2012

5 Liao W, "Therapeutic benefit of human umbilical cord derived mesenchymal stromal cells in intracerebral hemorrhage rat: implications of antiinflammation and angiogenesis" 24 : 307-316, 2009

6 Caplan AI, "The MSC: an injury drugstore" 9 : 11-15, 2011

7 Lindvall O, "Stem cells for the treatment of neurological disorders" 441 : 1094-1096, 2006

8 Tian L, "Shedded neuronal ICAM-5 suppresses T-cell activation" 111 : 3615-3625, 2008

9 Wang J, "Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage" 54 : 655-664, 2003

10 Figiel I, "Pro-inflammatory cytokine TNF-alpha as a neuroprotective agent in the brain" 68 : 526-534, 2008

11 Wang J, "Preclinical and clinical research on inflammation after intracerebral hemorrhage" 92 : 463-477, 2010

12 Gonzales NR, "Ongoing clinical trials in intracerebral hemorrhage" 44 : S70-S73, 2013

13 Sansing LH, "Neutrophil depletion diminishes monocyte infiltration and improves functional outcome after experimental intracerebral hemorrhage" 111 : 173-178, 2011

14 Aronowski J, "Molecular pathophysiology of cerebral hemorrhage: secondary brain injury" 42 : 1781-1786, 2011

15 Taylor RA, "Microglial responses after ischemic stroke and intracerebral hemorrhage" 2013 : 746068-, 2013

16 Bernardo ME, "Mesenchymal stromal cells: sensors and switchers of inflammation" 13 : 392-402, 2013

17 Matthew B Murphy, "Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine" 생화학분자생물학회 45 : 1-16, 2013

18 Smith AM, "M-CSF increases proliferation and phagocytosis while modulating receptor and transcription factor expression in adult human microglia" 10 : 85-, 2013

19 Keep RF, "Intracerebral haemorrhage:mechanisms of injury and therapeutic targets" 11 : 720-731, 2012

20 Qureshi AI, "Intracerebral haemorrhage" 373 : 1632-1644, 2009

21 Greenhalgh AD, "Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology" 5 : 823-833, 2012

22 Zhou Y, "Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation" 115 : 25-44, 2014

23 van Asch CJ, "Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and metaanalysis" 9 : 167-176, 2010

24 Ziai WC, "Hematology and inflammatory signaling of intracerebral hemorrhage" 44 : S74-S78, 2013

25 Morgenstern LB, "Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association" 41 : 2108-2129, 2010

26 Ruprecht K, "Effects of oncostatin M on human cerebral endothelial cells and expression in inflammatory brain lesions" 60 : 1087-1098, 2001

27 Jiang Y, "Effects of brain-derived neurotrophic factor on local inflammation in experimental stroke of rat" 2010 : 372423-, 2010

28 Minghetti L, "Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases" 63 : 901-910, 2004

29 Chu K, "Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death" 24 : 926-933, 2004

30 Linker R A, "CNTF is a major protective factor in demyelinating CNS disease: a neurotrophic cytokine as modulator in neuroinflammation" 8 : 620-624, 2002

31 Zhang R, "Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury" 10 : 106-, 2013