Table 1.
Preclinical studies of MSC therapy for hemorrhagic stroke
| MSC source | Species | Stroke model | Dose, administration, and timing | Results | Ref |
|---|---|---|---|---|---|
| Human, bone marrow | Male Wistar rats (270–320 g) | 100 µl autologous whole blood into right striatum | 3 × 106, 5 × 106 and 8 × 106 cells, by tail vein injection, one day post-ICH | Improvement in NSS; reduced striatal tissue loss; presence of newly formed immature neurons | 58 |
| Rat, bone marrow | Sprague-Dawley rats (270–300 g), unknown sex | Collagenase type VII into left caudate nucleus | 2 × 106 cells, by carotid artery/ cervical vein/ lateral ventricle injection, on days 1, 3, 5 and 7 after ICH | Improved limb motor function | 30 |
| Human, adipose | Male Sprague-Dawley rats (200–220 g) | Collagenase type VII into striatum | 3 × 106 cells, by IV injection, 24 h post-ICH | Improvement in modified limb placing behavioral scores; reduced brain atrophy and glial proliferation; endothelial marker expression but not neuronal or glial markers; acute brain inflammation markers | 64 |
| Human, processed lipoaspirate (or adipose-derived) | Male Wistar rats (422 ± 28.9 g) | Collagenase type IV into caudate nucleus | 3 × 106 cells, by tail vein injection, 24 h post-ICH | Improvement in Rotarod test; no lesion size difference; increase in endogenous progenitor cells | 31 |
| Human, bone marrow | Male Wistar rats (270–320 g) | 100 µl autologous whole blood into right striatum | 1 × 106 cells, by internal carotid artery injection, 24 h post-ICH | No improvement in NSS and corner turn tests from MSC therapy alone (only in combination with mannitol); no striatal tissue loss; presence of newly formed immature neurons | 32 |
| Human, umbilical cord | Male Sprague-Dawley rats (230–260 g) | Collagenase type VII into striatum | 2 × 105 cells, by intracerebral injection, 24 h post-ICH | Improvement in mNSS and Morris water maze test; injury area significantly reduced; vascular density increased; reduced number of degenerating neurons in peri-ICH area; attenuated immune response | 33 |
| Human, umbilical cord *with gene transduction of fibroblast growth factor and hepatocyte growth factor (HGF) | Male Sprague-Dawley rats (mean of 220 g) | Collagenase into internal capsule | 6 × 105 cells, by intracerebral injection, one week post-ICH | Improvement in Rotarod test; reduced demyelination | 34 |
| Human, bone marrow | Male macaca fascicularis monkeys (4.2 ± 0.2 kg) *first in primate | 1.5 mL of autologous arterial blood between the right cortex and basal ganglia | (1–5) x 106 cells, by intracerebral injection, 1 week or 4 weeks post-ICH | Improvement in modified Kito score scale; reduced tissue damage; higher microvessel density | 51 |
| Rat, bone marrow (overexpressing GDNF) | Wistar rats (270–320 g), unknown sex | Collagenase type I (0.25 U) and 1 U heparin sodium into right striatum | 5 × 105 cells, by intracerebral injection, 3 days post-ICH | Improvement in mNSS; reduced lesion volume | 65 |
| Rat, bone marrow | Female Wistar rats (275–300 g) | 0.3 mL of blood into the subarachnoid space *first SAH model | 3 × 106 cells, by tail vein injection, 24 h post-SAH | Improvement in mNSS; increased numbers of proliferating cells; fewer apoptotic cells | 48 |
| Rat, bone marrow | Female Wistar rats (200–250 g) | Collagenase type IV into the striatum | 2 × 106 cells, by intracerebral injection, 2 h post-ICH | Enhanced endogenous neurogenesis; reduced apoptosis of newborn neural cells | 47 |
| Rat, bone marrow | Male Sprague-Dawley rats (270–320 g) | Collagenase type VII into the striatum | 1 × 106 cells, by tail vein injection, one hour post-ICH | Improvement in mNSS; reduced hemorrhage volume; presence of newly formed immature neurons; elevated BDNF | 35 |
| Human, adipose | Male Sprague-Dawley rats (200–250 g) | Collagenase type VII into the striatum | 1 × 106 cells, by right femoral vein injection, 24 h post-IHC | Improvement in mNSS | 36 |
| Human, umbilical cord | Male Sprague-Dawley rats (postnatal day 4 – weight unknown) | 200 µL fresh maternal whole blood ventricles (100 µL into each ventricle) | 1 × 105 cells, by intracerebral injection, 24 h post-ICH | Prevented PHH development; attenuated impairment on negative geotaxis tests and Rotarod test; reduced corpus callosum loss; increased astrogliosis; increased expression of inflammatory cytokines | 59 |
| Human, bone marrow | Male Sprague-Dawley rats (190–210 g) | collagenase type VII into striatum | 2 × 105 cells, by intracerebral injection, 1 day post-ICH | Improvement in mNSS; decreased brain water content; reduced neutrophil infiltration and microglial activation in the peri-ICH area; downregulation of inflammatory mediators | 37 |
| Rat, bone marrow | Female Wistar rats (200–250 g) | Collagenase type IV (0.5 IU) into striatum | 5 × 106 cells, by intracerebral injection, 2 months post-ICH | Improvement in Rotarod and Video-Tracking-Box tests; increased endogenous neurogenesis | 38 |
| Rat, bone marrow | Female Wistar rats (275–300 g) | Unheparinized blood into subarachnoid space | 3 × 106 cells, by tail vein injection, 24 h post-ICH | Improvement in structural integrity of cerebral tissues (electron microscopy) | 68 |
| Rat, bone marrow | Male Sprague-Dawley rats (250–300 g) | Collagenase type IV | 3 × 106 cells, by IV injection, two hours post-ICH | Reduced brain edema and blood brain barrier leakage; decreased levels of proinflammatory cytokines; reduced apoptosis; downregulated density of microglia/macrophages and neutrophil infiltration at the ICH site; attenuated ONOO- formation; increased levels of ZO-1 and claudin-5 | 67 |
| Human, umbilical cord | Male Sprague-Dawley rats (250–300 g) | Collagenase type VII into the striatum | 5 × 105 cells, by intracerebral injection, 2 days post-ICH | Improvement in Rotarod tests; reduced lesion volume; increased angiogenesis; reduced inflammatory factors | 66 |
| Human, Wharton’s jelly (umbilical cord) *primed for 72 h into neuron-like cells | Male Sprague-Dawley rats, (240–280 g) | Collagenase type IV into striatum | 2 × 105 cells, by intracerebral injections, 1 week post-ICH | Improvement in Rotarod and limb placing test; increased blood vessel density; increased GDNF in primed cells | 43 |
| Rat, bone marrow *with hypoxic preconditioning | Male C57BL/6 mice (25–28 g) | Collagenase type IV | 1 × 106 cells, by intranasal delivery, 3 and 7 days post-IHC | Improvement in mNSS, Rotarod test, adhesive removal test, and locomotor function evaluation; reduction in tissue loss; reduction in ventricular enlargement; rescued levels of growth factors; enhanced proliferation and number immature neurons | 45 |
| Rat, bone marrow | Male Spontaneously Hypertensive Rat, unknown weight | 50 µL of autologous blood | 1 × 106 cells, by tail vein injection, timing not recorded | Improvement in mNSS and modified limb placing test; attenuated blood brain barrier permeability; increased levels of tight junction associated protein occludin, and type IV collagen | 52 |
| Human, umbilical cord *with hematoma aspiration | Male Sprague-Dawley rats (250–280 g) | Collagenase type IV into caudate nucleus | 1 × 105 by intracerebral injection, 6 h post-ICH (with hematoma aspiration) | Improvement in mNSS; reduced p53 expression around hematoma | 44 |
| Human, umbilical cord *compares IV and IC administration | Male Sprague-Dawley rats (230–260 g) | Collagenase type VII into the striatum | 2 × 105 cells by intracerebral injection. 2 × 106 cells by the tail vein injection - timing not recorded | Improvement in mNSS; reduced injury volume; increased vascular density in intracerebral administration group | 46 |
| Human, amniotic membrane | Male Wistar rats (240–260 g) | Collagenase type VII into the striatum | 5 × 105 cells, by intracerebral injection, 24 h post-ICH | Improvement in mNSS; increased blood vessel density; reduced apoptosis; increased proliferation and differentiation of neurons; increased growth factor levels; reduced neutrophil infiltration and microglial activation | 39 |
| Rat, bone marrow *compared to conditioned media | Male Sprague-Dawley rats (250–280 g) | 100 µl autologous arterial blood into right basal ganglia | Dose not reported, by tail vein injection, immediately post-ICH. | Improvements in forelimb-placing, corner turn tests, and mNSS; no effect on Morris water maze performance; reduced brain water content; increased phosphorylation of downstream signaling molecules; decreased inflammatory cytokines | 56 |
| Rat, bone marrow *with 2nd messenger signaling inhibitors | Male rats (250–280 g) | 100 µl autologous arterial blood into right basal ganglia | Dose not reported, by IV injection, 1 and 24 h post-ICH. | Improvement in mNSS which are blocked by inhibitor treatment; attenuation of second messenger signaling by inhibitors | 57 |
| Rat, bone marrow | Male Spontaneously Hypertensive Rats (250–300 g) | 20 µl of hemoglobin into right caudate nucleus | 1 × 106 cells, by intracerebral injection, 6 h post-ICH | Improvements in mNSS and modified limb placing test; reduced brain water content; reduced apoptosis; increased ZO-1 staining; reduced microglial activation; decreased inflammatory cytokines | 40 |
| Human, bone marrow *MSCs to prevent aneurysmal rupture | Male C57BL/6 J mice, weight unknown | Deoxycorticosterone acetate-salt to induce systemic hypertension. Elastase into the right basal cistern | 1 × 106 cells, by IV injection, 6 and 9 days after aneurysm induction | Reduced both the incidence of ruptured aneurysms and rupture rate | 50 |
| Human, placenta derived | Male Sprague-Dawley rats (250–350 g) | Collagenase type IV into striatum | 1 × 106 cells, by tail vein injection, one hour post-ICH | Decreased mortality rate; reduced hematoma volume and ventricular enlargement; reduced brain edema; increased ZO-1 and occludin | 41 |
| Rat, bone marrow | Male Wistar rats (300–350 g) | Perforation of the Circle of Willis | 1.5 × 106 cells, by intranasal delivery, 6 days post-SAH | Improvement in sensorimotor and mechanosensory function; reduced gray and white matter loss; increased activation of astrocytes and microglia | 61 |
mNSS modified neurological severity score, BDNF brain-derived neurotrophic factor, BM bone marrow, MSC mesenchymal stem cell, GDFN glial cell-derived neurotrophic factor, SAH subarachnoid hemorrhage, ICH intracerebral hemorrhage, IC intracerebral, IV intravenous, ZO-1 zonula occludens protein-1, ONOO- peroxynitrite, PHH post-hemorrhagic hydrocephalus