Neurotrauma and mesenchymal stem cells treatment: From experimental studies to clinical trials

Table 1 Summary of pre-clinical studies using mesenchymal stem cell for spinal cord injury

Animal	Lesion type	Cells source	Route of administration	Effects on CNS regeneration	Ref.
Rat	Contusion	Human mesenchymal precursor cells	Lesion site	Improvement in functional recovery and tissue sparing and reduction of cyst volume	[35]
Rat	Contusion	Human bone marrow-MSC	Lesion site , intracisternal, intravenous	Improvement in functional recovery	[36]
Rat	Hemisection	Bone marrow-MSC induced into Schwann Cells	Lesion site	Improvement in locomotor and sensory scores, axonal regeneration and remyelination	[37]
Rat	Contusion	Bone marrow-MSC	Lesion site , intravenous	Improvement in locomotor scores and NGF expression	[38-40]
Rat	Transection to the dorsal columns and tracts	Bone marrow-MSC, adipose derived-MSC	Lesion site	Improvement in locomotor scores, increased angiogenesis, preserved axons, decreased numbers of ED1-positive macrophages and reduced lesion cavity formation	[41]
Rat	Hemisection	Human umbilical cord-derived MSC	Lesion site	Suppress mechanical allodynia, and this effect seems to be closely associated with the modulation of spinal cord microglia activity and NR1 phosphorylation	[42,43]
Rat	Hemisection	Human bone marrow-MSC	Lesion site	Improvement in locomotor scores, shorter latency of somatosensory-evoked potentials and differentiation into various cells types	[44]
Rat	Hemisection	Bone marrow-MSC	Lesion site	Improvement in locomotor scores and reduced lesion cavity formation	[45]
Mouse	Compression	Bone marrow-MSC	Lesion site	Improvement in locomotor and sensory scores and reduced lesion volume	[46]
Rat	Contusion	Human bone marrow-MSC	Lesion site	Improvement in functional recovery, tissue sparing and reduction in the volume of lesion cavity and in the white matter loss	[35,47-49]
Rat	Contusion	Human umbilical cord-MSC	Lesion site	Improvement in functional recovery, reduction of the extent of astrocytic activation and increased axonal preservation	[50]
Dog	Compression	Bone marrow, adipose, Wharton’s jelly, umbilical cord derived-MSC	Lesion site	Improvement in functional recovery, increased numbers of surviving neurons, smaller lesion sizes and fewer microglia and reactive astrocytes in the epicenter of lesion	[51]
Rat	Compression	Bone marrow-MSC	Intravenous	Improvement in functional recovery, increase of NGF expression, higher tissue sparing and density of blood vessels	[52]
Rat	Contusion	Human umbilical cord-MSC	Lesion site	Improvement in functional recovery, endogenous cell proliferation and oligogenesis, and smaller cavity volume	[53,54]
Rat	Transection	Human-MSC	Lesion site	Improvement in functional recovery, increased amplitude of motor-evoked potentials, differentiation into neural cells	[55,56]
Rat	Contusion	Bone marrow-MSC	Lesion site	Improvement in functional recovery, preservation of axons, less scar tissue formation and increase in myelin sparing; higher levels of IL-4 and IL-3 and higher numbers of M2 macrophages, and reduction in TNF-α and IL-6 levels, and in numbers of M1 macrophages	[57-60]
Dog	Compression	Neural-induced adipose derived-MSC	Lesion site	Improvement in functional recovery and neuronal regeneration, and reduction of fibrosis	[61]
Mouse	Transection	Bone marrow-MSC	Lesion site	Improvement in functional recovery and neuronal survival, reduction of cavity volume and attenuation of inflammation, promotion of angiogenesis and reduction of cavity formation	[62-64]
Rat	Compression	Bone marrow-MSC	Lesion site	Improvement in functional recovery, up-regulation of VEGF mRNA expression, increase in angiogenesis and prevention of tissue atrophy	[65-67]
Rat	Compression	Human umbilical cord-MSC	Lesion site	Improvement in functional recovery, increase in the intensity of 5-HT fibers and in the volume of spared myelination; decrease in the area of the cystic cavity	[68]
Dog	Compression	Umbilical cord-MSC	Lesion site	Improvement in functional recovery, promotion of neuronal regeneration and reduction of fibrosis	[69]
Dog	Compression	Human umbilical cord-MSC	Lesion site	Improvement in functional recovery and remyelination	[70]
Rat	Contusion	Bone marrow-MSC	Intrathecal	Improvement in functional recovery	[71]
Rat	Contusion	Human bone marrow-MSC	Lesion site , lumbar puncture	Improvement in functional and sensory recovery	[72]
Rat	Contusion	Neural differentiated and undifferentiated MSC	Lesion site	Improvement in functional recovery and reduction of cavitation	[73]

CNS: Central nervous system; MSC: Mesenchymal stem cell; TNF: Tumor necrosis factor; IL: Interleukin; NGF: Nerve growth factor; VEGF: Vascular endothelial growth factor.

Table 2 Summary of clinical trials studies using mesenchymal stem cell for spinal cord injury

Title	Lesion type	Cells source	Phase of the study	Status	Effects on CNS regeneration
Clinical study of treatment for acute SCI using cultured bone marrow stromal cells	Cervical SCI	Autologous Bone marrow-MSC	Terminated	1/2	Rapid and remarkable recovery of ASIA B and C patients, but gradual or limited in ASIA A patients.
Autologous mesenchymal stem cell in SCI patients	Complete cervical or thoracic SCI	Autologous bone marrow-MSC	Enrolling by invitation	2	Not informed
Different efficacy between rehabilitation therapy and umbilical cord derived MSCs transplantation in patients with chronic SCI in China	Traumatic SCI	Umbilical cord derived-MSC	Recruiting	3	Not informed
A phase III/IV clinical trial to evaluate the safety and efficacy of bone marrow-derived MSC transplantation in patients with chronic SCI	Cervical SCI	Autologous bone marrow-MSC	Recruiting	1/2	Not informed
Phase I/II trial of autologous bone marrow derived MSCs to patients with SCISafety of autologous adipose derived MSCs in patients with SCI	Traumatic thoracic or lumbar SCIClinical diagnosis of SCI (ASIA A to C)	Autologous bone marrow-MSCAutologous Adipose derived-MSC	RecruitingCompleted	1/21	Not informed
The effect of intrathecal transplantation of autologous adipose tissue derived MSCs in the patients with SCI, phase I clinical study	Clinical diagnosis of SCI	Autologous Adipose derived-MSC	Recruiting	1	Not informed
Phase I, single center, trial to assess safety and tolerability of the intrathecal infusion of ex-vivo expanded bone-marrow derived MSCs for the treatment of SCI	Clinical diagnosis of SCI (ASIA A)	Autologous bone marrow-MSC	Active, not recruiting	1	Not informed
Study the safety and efficacy of bone marrow derived autologous cells for the treatment of SCI	Clinical diagnosis of SCI	Autologous bone marrow-MSC	Recruiting	1/2	Not informed
Surgical transplantation of autologous bone marrow stem cells with glial scar resection for patients of chronic SCI and intra-thecal injection for acute and subacute injury-a preliminary study	Complete spinal cord trans-section	Autologous bone marrow-MSC	Completed	1/2	Not informed
To study the safety and efficacy of autologous bone marrow stem cells in patients with SCI	SCI below C5 (ASIA A to C)	Autologous bone marrow-MSC	Recruiting	1/2	Not informed
Safety of autologous stem cell treatment for SCI in children	Clinical diagnosis of SCI (ASIA A to D)	Bone marrow-MSC	Recruiting	1	Not informed
Autologous bone marrow derived cell transplant in SCI patients	Traumatic SCI	Autologous bone marrow-MSC	Completed	1/2	Not informed
Phase 1 study of autologous bone marrow stem cell transplantation in patients with SCI	Traumatic thoracic or lumbar SCI	Autologous bone marrow-MSC	Not informed	1	Not informed
Phase I pilot study to evaluate the security of local Administration of autologous stem cells obtained from the bone marrow stroma, in traumatic injuries of the spinal cord	Traumatic SCI between C3 and L1	Autologous bone marrow-MSC	Recruiting	1	Not informed
Feasibility and safety of umbilical cord blood cell transplant into injured spinal cord: an open-labeled, dose-escalating clinical trial	Chronic SCI between C5 and T11 (ASIA A)	Umbilical cord blood mononuclear derived-MSC	Active, not recruiting	1/2	Not informed
Efficacy difference between rehabilitation therapy and umbilical Cord derived transplantation in patients with acute or chronic SCI in China	Clinical diagnosis of SCI	Umbilical cord derived-MSC	Not informed	2	Not informed
Safety and feasibility of umbilical cord blood cell Transplant Into Injured Spinal cord: an open-labeled, dose-escalating clinical trial	Chronic SCI between C5 and T11 (ASIA A)	Umbilical cord derived-MSC	Active, not recruiting	1/2	Not informed
Safety and effect of lithium, umbilical cord blood cells and the combination in the treatment of acute and sub-acute spinal cord injury : a randomized, double-blinded placebo-controlled clinical trial	Acute or Subacute traumatic SCI between C5 and T11 (ASIA A)	Umbilical cord derived-MSC	Active, not recruiting	1/2	Not informed

MSC: Mesenchymal stem cell; CNS: Central nervous system; SCI: Spinal cord injury.

Table 3 Summary of pre-clinical and clinical studies using mesenchymal stem cell for peripheral nerve injury

Animal	Nerve	Lesion type	Cells source	Route of administration	Ref.
Mouse	Median	Transection	Bone marrow-MSC	Local	[147]
Mouse	Ischiatic	Transection	Bone marrow-MSC	Local	[148]
Mouse	Ischiatic	Transection	Embryonic stem cell derived-MSC	Local	[144]
Mouse	Ischiatic	Crush	Adipose derived-MSC	Intravenous	[149]
Mouse	Ischiatic	Transection	Bone marrow-MSC	Local	[131]
Rat	Ischiatic	Crush	Amniotic fluid derived-MSC	Local	[150]
Rat	Ischiatic	Crush	Amniotic fluid derived-MSC	Intravenous	[151-153]
Rat	Facial	Transection	Bone marrow-MSC	Local	[154,155]
Rat	Ischiatic	Crush	Bone marrow-MSC	Local	[156]
Rat	Ischiatic	Transection	Adipose derived-MSC	Local	[157-159]
Rat	Ischiatic	Transection	Umbilical cord derived-MSC	Local	[160,161]
Rat	Ischiatic	Transection	Bone marrow-MSC	Local	[145,158,162-169]
Rat	Cavernous	Traction	Bone marrow-MSC	Intracavernousal injection	[170]
Rabbit	Facial	Transection	Bone marrow-MSC	Local	[171]
Rabbit	Ischiatic	Traction	Bone marrow-MSC	Local	[172,173]
Pig	Ischiatic	Transection	Bone marrow-MSC	Local	[174]
Dog	Ischiatic	Transection	Bone marrow-MSC	Local	[140,175]
Dog	Ischiatic	Transection	Adipose derived-MSC	Local	[176]
Monkey	Median	Transection	Bone marrow-MSC	Local	[142]
Human	Median or ulnar	Transection	Bone marrow mononuclear cell fraction-MSC	Local	[146]

MSC: Mesenchymal stem cell.