Table 1.
List of summarized manuscripts
| Over-expressed gene | Animal model | Type of ischemia | Type of stem cell | Root of administration | Time of transplantation after stroke | Number of transplanted cells | Evaluated parameters (employed method [time of evaluation after transplantation]) | Key findings | Reference |
|---|---|---|---|---|---|---|---|---|---|
| Neurotrophins | |||||||||
| BDNF | Adult male Wistar rats | MCAO (90 min) | Human BM-MSCs | Intra-striatum (ipsilateral) | 1 day | 5 × 105 |
1. Functional recovery (limb placement and treadmill tests [7d, 14d]) 2. Infarct size (MRI [1d, 6d, 13d]) 3. Apoptosis (TUNEL [6d]) 4. Differentiation (NeuN and GFAP staining [6d]) |
• Functional recovery: CTRL = MSCs < MSCsBDNF • Infarct size: CTRL = MSCs > MSCsBDNF • Apoptotic cells: CTRL = MSCs > MSCsBDNF |
[39] |
| BDNF | Adult male Sprague–Dawley rats | Permanent MCAO | Human BM-MSCs | IV | 6 h | 1 × 107 |
1. Functional recovery (treadmill stress test [24 h, 72 h, 7d]) 2. Infarct size (MRI [6 h, 24 h, 72 h, 7d]; TTC staining [7d]) 3. Differentiation (NeuN, NF and GFAP staining [7d]) |
• Functional recovery: CTRL < MSCs < MSCsBDNF • Infarct size: CTRL > MSCs > MSCsBDNF |
[40] |
| BDNF | Adult mice (gender not defined) | Intracerebral hemorrhage (injection of collagenase type IV into striatum) | Human neural stem cell line (HB1.F3) | Intra-striatum (ipsilateral) | 7 days | 2 × 105 |
1. Functional recovery (rotarod and limb placement tests [1d, 7d, 14d, 21d, 28d, 35d, 42d, 49d, 56d]) 2. Survival (HuNuA staining [14d, 56d]) 3. Differentiation (NF-L, NF-H, MAP2, GFAP staining [14d, 56d]) 4. Angiogenesis (vWF staining [14d, 56d]) 5. Apoptosis (TUNEL staining [56d]) 6. Gene expression (Western blot analyses of p53, p21, caspase-3, Bcl-2, Akt1 [14d, 56d]) |
• Functional recovery: CTRL < NSCs < NSCsBDNF • Survival: NSCs < NSCsBDNF • Angiogenesis: NSCs < NSCsBDNF • Apoptotic cells: CTRL > NSCs > NSCsBDNF • Expression of pro-apoptotic proteins: CTRL > NSCs > NSCsBDNF |
[41] |
| BDNF | Adult male Sprague–Dawley rats | MCAO (120 min) | Rat neural stem cells | Intra-striatum (ipsilateral) | 3 days | 5 × 107 |
1. Functional recovery (mNSS [14d, 28d, 42d, 56d, 70d, 84d]) 2. Survival (BrdU and BDNF staining [7d]) 3. Differentiation (neurofilament staining [84d]) |
Functional recovery: CTRL < NSCs < NSCsBDNF |
[42] |
| BDNF | Female Sprague–Dawley rats | MCAO (40 min) | Human amniotic mesenchymal cells (hAMSCs) | Intra-striatum (ipsilateral) | 1 day | 8 × 105 |
1. Functional recovery (neurologic, beam walking and rotarod tests [3d, 6d, 9d, 12d, 15d, 18d, 21d]) 2. Infarct size (TTC staining [21d]) 3. Differentiation (MAP2 and Nestin staining [21d]) 4. Gene expression (Western blot analysis of caspase-3 and iNOS [21d]) |
• Functional recovery: CTRL < hAMSCs < hAMSCsBDNF • Infarct size: CTRL > hAMSCs = hAMSCsBDNF • Expression of caspase-3 and iNOS: CTRL > hAMSCs |
[43] |
| BDNF | Adult male Sprague–Dawley rats | MCAO (90 min) | Human neural stem cell line (HB1.F3) | Intra-striatum (contralateral) | 7 days | 4 × 105 |
1. Functional recovery (rotarod, stepping and mNSS tests [7d, 14d, 21d, 28d, 35d, 42d, 49d, 56d]; apomorphine-induced rotation test [14d, 28d, 42d, 56d]) 2. Survival and migration (MRI [5d, 18d, 32d]; HNu and hMito staining [56d]) 3. Differentiation (nestin, DCX, NeuN, TH, GAD65/67, DARPP-32, CXCR4, vWF, PCNA staining [56d]) |
Functional outcome: CTRL < NSCsBDNF |
[44] |
| BDNF | Adult male Sprague-Dawley rats | MCAO (90 min) | Human BM-MSCs | Intra-striatum (ipsilateral) | 3 days | 5 × 105 |
1. Functional recovery (rotarod and adhesive-removal tests [4d, 11d, 25d]) 2. Infarct size (staining [11d]) 3. Differentiation (DCX and NeuN staining [4d, 25d]) 4. Apoptosis (TUNEL staining [11d]) |
• Functional recovery: CTRL < MSCs < MSCsBDNF • Infarct size: CTRL > MSCs > MSCsBDNF • Endogenous neurogenesis: CTRL < MSCs < MSCsBDNF • Apoptotic cells: CTRL > MSCs > MSCsBDNF |
[45] |
| BDNF, EGFL7, persephin or sonic hedgehog | Postnatal day 9, C57Bl/6J male and female mice | Right common carotid artery occlusion followed by exposure to 10 % oxygen in nitrogen (45 min) | Mouse MSCs | Intranasal | 10 days | 5 × 105 |
1. Functional recovery (cylinder rearing test [11d, 18d]) 2. Infarct volume (MAP2 and myelin basic protein staining [18d]) 3. Proliferation (BrdU and Ki67 staining [18d]) |
• Functional recovery: CTRL < MSCs < MSCsBDNF CTRL < MSCs < MSCsEGFL7 CTRL < MSCs > MSCspersephin CTRL < MSCs > MSCssonic hedgehog • Infarct size: CTRL > MSCsBDNF CTRL = MSCsEGFL7 CTRL = MSCspersephin |
[46] |
| BDNF or/and Noggin | Sprague Dawley rats | MCAO (60 min) | Rat BM-MSCs | IV | 1 day | Not defined |
1. Functional recovery (mNSS [7d]) 2. Gene expression (Western blot and IHC analyses of VEGF, BAX, Bcl2, GSK3β, p-GSK3β, Akt, p-Akt, TLR4 and MyD88 [7d]; ELISA analyses of MMP-9 and ROS [7d]). |
• Functional recovery: CTRL < MSCs < MSCsBDNF MSCs-Noggin < MSCsBDNF−Noggin • VEGF, Bcl-2, p-GSK3β, p-Akt expression: CTRL < MSCs < MSCsBDNF/Noggin • Bax, TLR4, MyD88 expression: CTRL > MSCs > MSCsBDNF/Noggin • MMP-9 and ROS expression: CTRL > MSCs > MSCsBDNF/Noggin>MSCsBDNF−Noggin |
[11] |
| NT-3 | Postnatal day 7, CD1 mice | Right common carotid artery occlusion followed by 2-3 h exposure to 8 % O2 and 92 % N2 | Mouse neural stem cells (C17.2 cell line) |
Two sites at ipsilateral infarcted hemisphere OR the contralateral lateral ventricle |
3 days |
3 × 105 (ipsillateral hemisphere); 1 × 105 (contralateral lateral ventricle) |
1. Functional recovery (treadmill stress test [1d, 3d, 5d, 7d, 11d, 15d, 19d, 23d, 27d, 31d]) 2. Differentiation (NeuN, MAP2, neurofilament, CNPase, O1, GFAP, glutamate, GABA and vesicular acetylcholine transporter staining [14-28d]) |
Functional recovery: CTRL < NSCs < NSCsNT3 |
[47] |
| NT-3 | Adult male Sprague–Dawley rats | MCAO (120 min) | Rat neural stem cells | Intra-striatum (ipsilateral) at 2 different sites | 7 days | 1 × 105at each site | Functional recovery (NSS [1d, 7d, 14d]) |
Functional recovery: CTRL < NSCs < NSCsNT3 |
[48] |
| Glial–derived neurotrophic factor | |||||||||
| GDNF, BDNF, NT3 or CNTF | Adult male Wistar rats | MCAO (90 min) | Human BM-MSCs | Intra-striatum (ipsilateral) | 1 day | 5 × 105 |
1. Functional recovery (limb placement test [7d, 14d]) 2. Infarct size (MRI [1d, 6d, 13d]; TTC staining [13d]) 3. Survival (discosoma red fluorescent protein [13d]) |
• Functional recovery: CTRL < MSCsBDNF, MSCsGDNF • Infarct size: CTRL > MSCsBDNF, MSCsGDNF • Survival: MSCs < MSCsBDNF, MSCsGDNF |
[49] |
| GDNF | Adult female Sprague-Dawley rats | Permanent MCAO | Human BM-MSCs | IV | 3 h | 1 × 107 |
1. Functional recovery Infarct size (MRI [3 h, 1d, 3d, 7d, 14d, 28d]; TTC staining [7d]) |
• Functional outcome: CTRL < MSCs < MSCsGDNF • Infarct size: CTRL > MSCs > MSCsGDNF |
[50] |
| GDNF | Adult male Wistar rats | MCAO (120 min) | Rat neural stem cells | Intra-lateral ventricle (ipsilateral) | 3 days | 5 × 105 |
1. Functional recovery (mNSS [4d, 11d, 18d, 32d, 46d]) 2. Infarct size (H&E [4d, 11d, 18d, 32d, 46d]) 3. Survival (GFP and BrdU staining [4d, 11d, 18d, 32d, 46d]) 4. Apoptosis (TUNEL [4d, 11d, 18d, 32d, 46d]) 5. Gene expression (IHC analyses of synaptophysin PSD-95 and caspase-3 [4d, 11d, 18d, 32d, 46d]; Western blot analyses of BDNF and NT-3 [4d, 11d, 18d, 32d, 46d]) |
• Functional recovery: CTRL < NSCs < NSCsGDNF • Infarct size: CTRL > NSCs > NSCsGDNF • Survival: NSCs < NSCsGDNF • Apoptotic cells: CTRL > NSCs > NSCsGDNF • Synaptophysin, PSD-95 and BDNF expression: NSCs < NSCsGDNF • Caspase-3 expression: NSCs > NSCsGDNF |
[51] |
| GDNF | Adult male spontaneous hypertensive rats | MCAO (120 min) | Human umbilical cord blood CD34 + cells | IV | 6 h | 1 × 107 |
1. Functional recovery (mNSS [1d, 7d, 14,d 21d, 28d] 2. Survival (GFP staining [7d, 28d]) 3. Infarct size (TTC staining [7d]) 4. Differentiation (NeuN, GFAP staining [7d, 28d]) |
• Functional recovery: CTRL < UCBCs < UCBCsGDNF • Survival: UCBCs < UCBCsGDNF • Infarct size: CTRL > UCBCs > UCBCsGDNF |
[52] |
| GDNF | Adult Sprague–Dawley rats | MCAO (120 min) | Rat BM-MSCs | IV | 3 days | 5 × 106 |
1. Functional recovery (ipsilateral circling, bilateral grasp and beam walking tests [3d, 14d, 28d]) 2. Apoptosis (TUNEL staining [3d, 14d, 28d]) 3. Gene expression (Bcl2 staining [3d, 14d]) |
• Functional recovery: CTRL < MSCs < MSCsGDNF • Apoptotic cells: MSCs > MSCsGDNF • Bcl2 expression: CTRL < MSCs < MSCsGDNF |
[53] |
| Angiogenic factors | |||||||||
| VEGF | Adult male Wistar rats | MCAO (120 min) | Rat BM-MSCs | Intra-striatum (ipsilateral) | 1 day | 1 × 106 |
1. Functional recovery (mNSS [2d, 6d, 13d, 20d, 27d]) 2. Infarct volume (TTC staining [13d]) 3. Brain water content ([1d, 6d]) |
• Functional recovery: CTRL < MSCs < MSCsVEGF • Infarct size: CTRL > MSCs > MSCsVEGF • Brain water content: CTRL = MSCs = MSCsVEGF |
[54] |
| VEGF | adult mice | Intracerebral hemorrhage ( injection of collagenase type IV into striatum) | Human neural stem cell line (HB1.F3) | Intra-striatum (ipsilateral) | 7 days | 2 × 105 |
1. Functional recovery (rotarod and modified limb placement tests [1d, 7d, 14d, 21d, 28d, 35d, 42d, 49d, 56d]) 2. Survival (HuNuA staining [14d, 56d]) 3. Differentiation (NF-L, NF-H, MAP2 and GFAP staining [56d]) 4. Angiogenesis (vWF staining [14d, 56d]) 5. Apoptosis (TUNEl staining [56d]) 6. Gene expression (Western blot analysis of caspase 3, Bax, Bcl-2, Bcl-xL, Akt1, PI3 kinase p85 and p110) |
• Functional recovery: CTRL < NSCs < NSCsVEGF • Survival: NSCs < NSCsVEGF • Angiogenesis: CTRL < NSCs < NSCsVEGF • Apoptotic cells: CTRL > NSCs • Pro-apoptotic expression: CTRL > NSCs, NSCsVEGF • Anti-apoptotic expression: CTRL < NSCs, NSCsVEGF |
[55] |
| Ang1 | Adult male Sprague–Dawley rats | Permanent MCAO | Human BM-MSCs | IV | 6 h | 1 × 106 |
1. Functional recovery (treadmill stress test [1d, 3d, 7d]) 2. Infarct size (MRI [1d, 3d, 7d]; TTC staining [7d]) 3. Angiogenesis (three-dimensional image acquisition [7d, 28d]) 4. Regional cerebral blood flow (perfusion weighted imaging [6 h, 3d, 7d]) |
• Functional recovery: CTRL < MSCs < MSCsAng1 • Infarct size: CTRL > MSCs = MSCsAng1 • Angiogenesis: CTRL < MSCs < MSCsAng1 • rCBF: CTRL < MSCs, MSCsAng1 |
[56] |
| Ang1, VEGF or Ang1 + VEGF | Adult male Sprague–Dawley rats | Permanent MCAO | Human BM-MSCs | IV | 6 h | 1 × 106 |
1. Functional recovery (treadmill stress test [1d, 3d, 7d, 14d]) 2. Infarct size (MRI [1d, 3d, 7d, 14d]; TTC staining [7d]). 3. Angiogenesis (three-dimensional image acquisition [7d]) 4. Differentiation (vWF staining [7d]) 5. Regional cerebral blood flow (perfusion weighted imaging [7d]) |
• Functional recovery: CTRL = MSCsVEGF<MSCs, MSCsAng<MSCsAng+VEGF • Infarct size: CTRL = MSCsVEGF>MSCs = MSCsAng>MSCsAng+VEGF • Angiogenesis: CTRL < MSCs = MSCsVEGF<MSCsAng<MSCsAng+VEGF • Differentiation: CTRL < MSCs = MSCsVEGF<MSCsAng<MSCsAng+VEGF • rCBF: CTRL, MSCsVEGF<MSCs, MSCsAng<MSCsAng−VEGF |
[57] |
| PlGF | Adult male Sprague–Dawley rats | Permanent MCAO | Human BM-MSCs | IV | 3 h | 1 × 107 |
1. Functional recovery (treadmill stress and limb placement tests [3 h, 1d, 3d, 4d, 7d]) 2. Infarct size (MRI [3 h, 6 h, 1d, 3d, 4d, 7d]; TTC staining [7d]) 3. Apoptosis (TUNEL staining [7d)] 4. Angiogenesis (three-dimensional image acquisition [7d]) |
• Functional recovery: CTRL < MSCs < MSCsPIGF • Infarct size: CTRL > MSCs > MSCsPIGF • Apoptotic cells: CTRL > MSCs > MSCsPIGF • Angiogenesis: CTRL < MSCs < MSCsPIGF |
[58] |
| HIF1α | Male Sprague-Dawley rats | MCAO (90 min) | Rat neural stem cells | Intra-lateral ventricle (ipsilateral) | 1 day | 1 × 106 |
1. Functional recovery (mNSS [6d, 13d, 20d, 27d]) 2. Survival (BrdU staining [34d]) 3. Differentiation (neurofilament and GFAP [34d]) 4. Angiogenesis (factor VIII [34d]) |
• Functional recovery: CTRL < NSCs < NSCsHIF1α • Survival: CTRL < NSCs < NSCsHIF1α • Angiogenesis: CTRL < NSCs < NSCsHIF1α |
[59] |
| HIF1α | Adult male Sprague–Dawley rats | Permanent MCAO | Rat BM-MSCs | IV | 3 h | 2 × 106 |
1. Functional recovery (mNSS [1d, 7d, 14d, 28d]; Morris water-maze test [14d, 28d]) 2. Infarct size (TTC staining [7d]) 3. Apoptosis (TUNEL staining in the hippocampus and cortex [7d]) 4. Gene expression/ differentiation (pax6/DCX staining in the hippocampus [7d] and cortex [14d]) |
• Functional recovery: CTRL < MSCs < MSCsHIF1α • Infarct size: CTRL > MSCs > MSCsHIF1α • Apoptotic cells: CTRL > MSCs > MSCsHIF1α • pax6/DCX expression: CTRL < MSCs < MSCsHIF1α |
[60] |
| HIF1α | Adult male Sprague Dawley rats | MCAO (120 min) | Rat BM-MSCs | IV | 6 h | 5 × 106 |
1. Functional recovery (mNSS [7d, 14d, 21d, 28d]) 2. Infarct size (TTC staining [1d, 14d, 28d]) 3. Gene expression (Western blot analysis of VEGF [7d, 14d, 28d]) 4. Microvessel density (CD105 staining [7d, 14d, 28d]) |
• Functional recovery: CTRL < MSCs < MSCsHIF1α • Infarct size: CTRL > MSCs > MSCsHIF1α • VEGF expression: CTRL < MSCs < MSCsHIF1α • Microvessel density: CTRL < MSCs < MSCsHIF1α |
[61] |
| HIF1α | Adult male Sprague-Dawley rats | MCAO (90 min) | Rat neural stem cells | Intra-cerebral (ipsilateral) | 1 day | 1 × 106 |
1. Functional recovery (mNSS [6d, 13d, 20d, 27d]) 2. Brain atrophy (Nissl staining [34d]) 3. Survival (BrdU staining [34d]) 4. Differentiation (NF-200 and GFAP staining [34d]) 5. Gene expression (VEGF and vWF staining [6d]) |
• Functional recovery: CTRL < NSCs < NSCsHIF1α • Brain atrophy: CTRL > NSCs > NSCsHIF1α • Survival: NSCs < NSCsHIF1α • VEGF and vWF expression: NSCs < NSCsHIF1α |
[62] |
| HIF1α | Male Sprague- Dawley rats | Left common carotid artery occlusion followed by exposure to 8 % oxygen in nitrogen (120 min) | Rat BM-MSCs | IV | 1 day | 5 × 105 |
1. Functional recovery (Morris water maze test [13d]) 2. Migration (Cm-Dil staining [6d, 13d, 20d]) 3. Histopathology (H&E [6d, 13d, 20d]) |
• Functional recovery: CTRL < MSCs < MSCsHIF1α • Migration: MSCs < MSCsHIF1α • Pathological changes: MSCs < MSCsHIF1α |
[63] |
| Trophic factors | |||||||||
| FGF2 | Adult male Wistar rats | MCAO (120 min) | Rat BM-MSCs | Intra-striatum (ipsilateral) | 1 day | 1 × 106 |
1. Functional recovery (mNSS [2d, 6d, 13d, 20d]) Infarct size (TTC staining [2d, 13d]) |
• Functional recovery: CTRL < MSCs < MSCsFGF2 • Infarct size: CTRL > MSCs > MSCsFGF2 |
[64] |
| FGF1 | Adult male Wistar rats | MCAO (30 min) | Rat adipose mesenchymal stem cells | IV | 30 min | 2 × 106 |
1. Functional recovery (rotarod and Roger’s tests [1d]) 2. Infarct size (TTC staining [1d]) 3. Apoptosis (TUNEL staining [1d]) |
• Functional recovery: CTRL < MSCs < MSCsFGF1 • Infarct size: CTRL > MSCs = MSCsFGF1 • Apoptotic cells: CTRL > MSCs > MSCsFGF1 |
[65] |
| FGF2 | Adult Sprague–Dawley male rats | MCAO (120 min) | Mouse neural stem cells (C17.2 cell line) | IV | 1 day | 5 × 106 |
1. Functional recovery (mNSS [1d, 3d, 7d, 10d, 14d, 21d, 28d]) 2. Infarct size (TTC staining [7d]) 3. Survival (cell tracker CM-DiI dye [28d]) 4. Differentiation (NeuN, GFAP and nestin staining [28d]) |
• Functional recovery: CTRL < MSCs < MSCsFGF2 • Infarct size: CTRL > MSCs = MSCsFGF2 • Survival: MSCs < MSCsFGF2 |
[66] |
| HGF | Adult male Wistar rats | MCAO (120 min) | Rat BM-MSCs | Intra-striatum (ipsilateral) | 2 or 24 h | 1 × 106 |
1. Functional recovery (mNSS [1d, 4d, 7d, 14d, 21d, 28d, 35d or 3d, 6d, 13d]) 2. Infarct size (TTC staining [3d, 14d]) 3. Apoptosis (TUNEL staining [7d]) |
• Functional recovery: CTRL < MSCs < MSCsHGF • Infarct size: CTRL > MSCsHGF • Apoptotic cells: CTRL > MSCs > MSCsHGF |
[67] |
| PEDF | Adult male Sprague–Dawley rats | MCAO (60 min) | Exosomes from PEDF over-expressing rat adipose stem cells | ICV | Daily for 3 days prior to MCAO |
1. Infarct size (TTC staining [3d after MCAO]) 2. Apoptosis (TUNEL staining [3d after MCAO]) 3. Gene expression (Western blot analyses of caspase-3, caspase-9 [3d after MCAO]) |
• Infarct size: CTRL > PEDF-exosome • Apoptotic cells: CTRL > PEDF-exosome |
[68] | |
| Survival/migration factors | |||||||||
| Akt-1 | Mice | Intracerebral hemorrhage (injection of collagenase type IV into striatum) | Human neural stem cell line (HB1.F3) | Intra-cortical (ipsilateral) | 7 days | 2 × 105 |
1. Functional recovery (rotarod and modified limb placement tests [1d, 7d, 14d, 21d, 28d, 35d, 42d, 49d, 56d]) 2. Survival (hNuMA staining [14d, 56d]) 3. Differentiation (NF-L, NF-H, MAP2, GFAP staining [56d]) |
• Functional recovery: CTRL < NSCs = NSCsAkt1 • Survival: NSCs < NSCsAkt1 |
[69] |
| Bcl-2 | Adult male Wistar rats | MCAO (120 min) | Mouse embryonic stem cells | Intra-cerebral at 4 different sites (ipsilateral) | 7 days | 2.5 × 104 at each site |
1. Functional recovery (NSS [1d, 7d, 14d, 21d, 35d]) 2. Survival (M2 and M6 staining [7d]) 3. Differentiation (NeuN, GFAP, neural/glial antigen-2, adenomatous polyposis coli, neurofilament staining [14d]) 4. Vascularization (Glut-1 staining [42d]) Apoptosis (TUNEL staining [3d]) |
• Functional recovery: CTRL < ESCs < ESCsBcl2 • Survival: ESCs < ESCsBcl2 • Differentiation: ESCs < ESCsBcl2 • Apoptotic cells: ESCs > ESCsBcl2 |
[70] |
| Bcl-2, Bcl-xl, Akt1, HIF1α, Bcl2 + Bcl-xl + Akt1 | Adult immunodeficient NOD/SCID-γ mice | Permanent MCAO | Human neural stem cells (H9 and RC17) | Intra-striatum or intra-cortical (unilateral) | 2 days | 5 × 104 at each site |
1. Functional recovery (latency-to-move, sticky-tape-removal and Collins tests [7d]) 2. Survival (EGFP staining [7d, 30d, 60d, 90d]) 3. Cell death (activated caspase-3 staining [5d]) 4. Proliferation (Ki-67 staining [7d, 30d, 60d, 90d]) 5. Differentiation (nestin [7d, 30d, 60d, 90d], NeuN [60d, 90d], Olig2 [60d, 90d], GFAP [60d, 90d] staining) |
• Functional recovery: NSCsBcl−xl> NSCs • Survival: NSCsAkt1= NSCsBcl2+Bcl−xl+Akt1> NSCsBcl2, NSCsBcl−xl> NSCsHIF1α> NSCs • Cell death: NSCs > NSCsengineered • Proliferation: NSCs > NSCsAkt1, NSCsBcl2+Bcl−xl+Akt1> NSCsBcl2, NSCsBcl−xl, NSCsHIF1α • Neuronal differentiation: NSCsBcl−xl> NSCs |
[71] |
| CXCR4 | Adult male Sprague– Dawley rats | MCAO (120 min) | Rat BM-MSCs | IV | 1 day | 2 × 106 |
1. Functional recovery (postural reflex and forelimb placing tests [6d]) 2. Infarct size (TTC staining [6d]) 3. Differentiation (vWF, neuron specific enolase and GFAP staining [6d]) 4. Angiogenesis (three-dimensional image acquisition [6d]) 5. Migration (In vivo migration assay [6d]) |
• Functional recovery: CTRL < MSCs < MSCsCXCR4 • Infarct size: CTRL > MSCs > MSCsCXCR4 • Angiogenesis: CTRL < MSCs < MSCsCXCR4 • Migration: MSCs < MSCsCXCR4 |
[72] |
| CXCR4 | Adult male Sprague–Dawley rats | MCAO (120 min) | Human BM-MSCs | IV | 1 day | 2 × 106 |
1. Functional recovery (mNSS [2d, 6d, 13d]) 2. Infarct size (MRI [13d]) 3. Survival (HuNuA staining [3d]) 4. Distribution (PCR [3d]) 5. Differentiation (NeuN, GFAP staining [3d]) |
• Functional recovery: CTRL < MSCs < MSCsCXCR4 • Infarct size: CTRL = MSCs = MSCsCXCR4 • Survival: MSCs < MSCsCXCR4 |
[73] |
| SOD1 | Adult male C57BL/6 mice | MCAO (45 min) |
Neural stem cells isolated from wild-type, SOD1 over-expressing and SOD1 knockout mice |
Intra-cortical at 3 different sites (ipsilateral) | 2 days | 1 × 105 at each site |
1. Functional recovery (mNSS and rotarod tests [5d, 12d, 19d, 26d]) 2. Survival (GFP staining [26d]) 3. Infarct size (H&E staining [26d]) 4. Apoptosis (TUNEL staining [2d]) 5. Differentiation (βIII-tubulin and GFAP staining [26d]) 6. Protein determination (ELISA analysis for VEGF level in the cortex [2d]) 7. Blood vessel density (DyLight 594-labeled lycopersicon esculentum lectin staining [12d]) |
• Functional recovery, rotarod test: CTRL < NSCs < NSCsSOD1 • Functional recovery, mNSS: CTRL = NSCs = NSCsSOD1 • Survival: NSCs < NSCsSOD1 • Striatal infarct size: CTRL = NSCs = NSCsSOD1 • Cortical infarct size: CTRL > NSCs > NSCsSOD1 • Apoptotic cells: NSCs > NSCsSOD1 • Differentiation: CTRL = NSCs = NSCsSOD1 • VEGF level: CTRL < NSCs < NSCsSOD1 • Blood vessel density: CTRL < NSCs < NSCsSOD1 |
[74] |
| IL10 | Adult male Sprague-Dawley rats | MCAO (90 min) | Human BM-MSCs | IV | 0 or 3 h | 1 × 106 |
1. Functional recovery (hemiparesis, abnormal posture and rotarod tests [7d]) 2. Infarct size (TTC staining [3d, 7d]) 3. Gene expression (ionized calcium binding adaptor molecule 1 and TNF-α staining [1d, 3d]) 4. Neuronal degeneration (fluoro-jade C staining [1d, 3d]) 5. Protein determination (ELISA analysis for TNF-α, IL-1β and IL-6 in the ischemic hemisphere [3d]) |
• Functional recovery: CTRL < MSCs < MSCsIL10 • Infarct size: CTRL > MSCs > MSCsIL10 • Pro-inflammatory cytokine expression: CTRL > MSCs > MSCsIL10 • Neuronal degeneration: CTRL > MSCs > MSCsIL10 |
[75] |
| SVV | Adult male Sprague-Dawley rats | MCAO (120 min) | Rat BM-MSCs | IV | 24 h | 3 × 106 |
1. Functional recovery (mNSS test [1d, 14d]) 2. Infarct size (TTC staining [14d]) 3. Survival (GFP staining [4d, 14d]) 4. Differentiation (NeuN staining [4d, 14d]) 5. Gene expression (Western blot analysis of VEGF and bFGF in injured cerebral tissues [4d, 14d]) |
• Functional recovery: CTRL < MSCs < MSCsSVV • Infarct size: CTRL > MSCs > MSCsSVV • Survival: MSCs < MSCsSVV • VEGF and bFGF expression: CTRL < MSCs < MSCsSVV |
[76] |
| MiR-133b | Adult male Wistar rats | MCAO (120 min) | Rat BM-MSCs | IV | 1 day | 3 × 106 |
1. Functional recovery (adhesive-removal and foot-fault tests [2d, 6d, 13d]) 2. Axonal plasticity (biotinylated dextran amine staining [13d]) 3. Neurite remodeling (Bielshowsky silver, NF-200, synaptophysin staining [13d]) |
• Functional recovery: CTRL < MSCs < MSCsmiR133 • Axonal density: CTRL < MSCs < MSCsmiR133 • Neurite remodeling: CTRL < MSCs < MSCsmiR133 |
[77] |
| MiR-133b | Adult male Sprague-Dawley | MCAO (90 min) | Rat BM-MSCs | IV | 3 days | 2 × 106 |
1. Functional recovery (mNSS [7d, 14d]) 2. Differentiation (NeuN staining [14d]) |
Functional recovery: CTRL < MSCsMiR133b |
[78] |
Ang1: Angiopoietin-1; BDNF: Brain-derived neurotrophic factor; CNTF: Ciliary neurotrophic factor; CXCR4: C-X-C chemokine receptor type 4; DARPP-32: Dopamine- and cAMP-regulated neuronal phosphoprotein; DCX: Doublecortin; FGF: Fibroblast growth factor; GAD65/67: Glutamic acid decarboxylase; GDNF: Glial cell-derived neurotrophic factor; GFAP: Glial fibrillary acidic protein; GFP: Green fluorescent protein; H&E: Hematoxylin and eosin; HGF: Hepatocyte growth factor; HIF1α: Hypoxia-inducible factor-1α; hMito: human mitochondria; HuNuA: Human nuclear matrix antigen; IHC: Immunohistochemistry; IL: Interleukin; iNOS: Inducible nitric oxide synthase; MCAO: Middle cerebral artery occlusion; mNSS: Modified neurological severity score; MRI: Magnetic resonance imaging; NeuN: Neuronal nuclei; NF: Neurofilament; NF-H: Neurofilament heavy chain; NF-L: Neurofilament light chain; NT-3: Neurotrophin-3; PCNA: Proliferating cell nuclear antigen; PCR: Polymerase chain reaction; PEDF: Pigment epithelium-derived factor; PlGF: Placental growth factor; rCBF: Regional blood flow; ROS: Reactive oxygen species; SOD: Copper/zinc-superoxide dismutase; SVV: Survivin; TH: Tyrosine hydroxylase; TNF-α: Tumor necrosis factor alpha; TTC: Triphenyl tetrazolium chloride; TUNEL: Terminal deoxynucleotidyl transferase dUTP nick end labeling; VEGF: Vascular endothelial growth factor; vWF: von Willebrand factor