Current status and future perspectives on stem cell transplantation for spinal cord injury

Table 1 American Spinal Cord Injury Association Impairment Scale improvement scale

A = Complete	No sensory or motor function is preserved in the sacral segments S4–S5
B = Sensory incomplete	Sensory but not motor function is preserved below the neurological level and includes the sacral segments S4-S5 (light touch or pin-prick at S4–S5 or deep anal pressure) AND no motor function is preserved more than three levels below the motor level on either side of the body
C = Motor incomplete	Motor function is preserved below the neurological level AND more than half of the key muscle functions below the neurological level of injury have a muscle grade less than 3 (grades 0–2)
D = Motor incomplete	Motor function is preserved below the neurological level AND at least half (half or more) of the key muscle functions below the neurological level of injury have a muscle grade ≥ 3
E = Normal	If sensation and motor function as tested with the ISNCSCI are graded as normal in all segments AND the patient has prior deficits, then the AIS grade is E. Someone without an initial SCI does not receive an AIS grade

Time from injury: Immediate: 0-2 h after the injury; acute: Early acute phase: 2-48 h; subacute: 2 d - 2 wk; intermediate: 2 wk - 6 mo; chronic phase: > 6 mo. AIS: American spinal injury association Impairment Scale; ISNCSCI: International Standards for Neurological Classification of SCI.

Table 2 Summary of the studies included in the systematic literature review focusing on bone marrow derived stem cells (i.e., BMSC)

Ref.	Phase of clinical trial	Patients (n)	Localization of injury	Pre-treatment AIS classification or level of injury	Stem cells		Treatment			Follow up (months)	Outcomes
					Origin	Type	Dose	Administration route	Time from Injury		Functional improvement	Adverse effects
Park et al[37], 2005	N/A	6	Cervical	AIS A	Autologous (iliac bone marrow)	BMSC	1.98 × 1010	Intralesional	N/A	6-18	AIS A→C 4, AIS A→B: 1, AIS A=A: 1	No serious adverse effects
Sykova et al[11], 2006	N/A	20	Cervical and thoracic	AIS A: 15; AIS B: 4; AIS C: 1	Autologous (iliac bone marrow)	BMSC	104.0 ± 55.3 × 108	Intravenous + Intraarterial	Subacute or chronic	24	AIS A→B: 1, AIS B→D: 1, AIS=: 15	No serious adverse effects
Chernykh et al[12], 2007	N/A	18	Cervical, Thoracic, Lumbar	N/A	Autologous (iliac bone marrow)	BMSC	N/A	Intralesional+ Intravenous	Chronic	9.4 ± 4.6	ASIA scale: significant increase in total sensitivity and motor activity score	No serious adverse effects
Yoon et al[13], 2007	I/II	35	Cervical (4) and thoracic (4)	N/A	Autologous iliac bone marrow	BMSC	1 × 108	Intralesional	Intermediate	10.4	AIS grade increased in 30.4% of the acute and subacute treated patients (AIS A→B or A→C)	No serious adverse effects
Geffner et al[14], 2008	N/A	8	Thoracic	AIS A: 5, AIS B: 1, AIS C: 2	Autologous iliac bone marrow	BMSC	1.2 × 106/kg	Intrathecal	4 acute and 4 chronic (average 114 months)	24	AIS A→C: 4, AIS B→C: 1, AIS C→D: 1 AIS =: 2	No serious adverse effects
Adel et al[38], 2009	N/A	43	Cervical and thoracic	AIS A: 40, AIS C: 3	Autologous iliac bone marrow	BMSC	5-10 × 106	Intrathecal	Chronic (average 43.2 months)	6	AIS A→B: 11; AIS A→C: 1; AIS B→C: 3; AIS =: 28	ADEM: 1/43; Marked increased spasticity: 4/43; Neuropathic pain: 24/43
Kumar et al[39], 2009	I/II	297	N/A	AIS A: 249, AIS B: 12, AIS C: 34, AIS D: 2	Autologous iliac bone marrow	BMSC	N/A	Intrathecal	N/A	18.4-20.5	32.7% of the ASIA-classified patients showed improvement, in sensory and motor scale	No serious adverse effects. Mild-to-moderate neuropathic pain in few patients
Pal et al[40], 2009	N/A	30	Cervical and thoracic	AIS A: 24, AIS C: 6	Autologous iliac bone marrow	BMSC	1 × 106/kg	Intrathecal	< 6 months: 20, > 6 months: 30	12-36	No changes in the ASIA scale, SSEP, MEP and NCV	No serious adverse effects. Neuropathic pain in two patients
Abdelaziz et al[41], 2010	N/A	20	Thoracic	AIS A: 10, AIS B: 5, AIS C: 5	Autologous iliac bone marrow	BMSC	5 × 106/kg	Intrathecal + Intralesional	Chronic (> 6 months)	12	AIS A→B: 1, AIS A→C: 2, AIS B→C: 3; AIS=: 14	No serious adverse effects.Headache (12) and fever (3)
Bhanot et al[30], 2011	N/A	13	Cervical and thoracic	AIS A	Autologous	BMSC	3-6-8 × 106/kg	Intrathecal	Intermediate and chronic (3-132 months, average 28)	6-38	AIS A→B: 1, Patchy improvement in sensations below the injured level: 2, Patient subjectively felt improved sense of bladder filling: 1	No serious adverse effects. Transient increase in spasticity in the lower limbs (50%)
Park et al[35], 2012	N/A	10	Cervical	AIS A: 4, AIS B: 6	Autologous iliac bone marrow	BMSC	8 × 106 (intralesional) + 4 × 107 (subdural)	Intralesional + Subdural	> 1 months	6-62	Improvements in ADL, SSEP, MEP (3/10, all AIS B)	No serious adverse effects
Karamouzian et al[18], 2012	I/II	11	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	0.7-1.2 × 106	Intrathecal	Acute and intermediate/chronic (max 1.5 months)	12-33	AIS A→C: 5, AIS=: 0	No serious adverse effects
Dai et al[28], 2013	N/A	20	Cervical	AIS A, ASIA score: 31.6 ± 9.82	Autologous iliac bone marrow	BMSC	2 × 107	Intralesional	Chronic (51.9 ± 18.3)	6	AIS A→B: 9, ASIA score: 43.1 ± 19.32	No serious adverse effects. Fever (2), Headache and dizziness (1), pain and numbness in spinal cord dominant area (2)
Jiang et al[19], 2013	N/A	20	Cervical (4), thoracic (11) and lumbar (5)	AIS A: 8, AIS B: 4, AIS C: 8	Autologous iliac bone marrow	BMSC	1 × 108	Intrathecal	Intermediate and chronic (3-120 months)	1	AIS A→B: 3, AIS A→C: 1, →AIS C→D: 8	No serious adverse effects. Fever and headache
Yazdani et al[42], 2013	I	8	Cervical (1) and thoracic (7)	AIS A	Autologous iliac bone marrow	BMSC	1 × 106	Intralesional	Chronic (13-63 months)	26-43	Although some improvement in light touch and pinprick sensation was observed, no improvement in ASIA classification was seen	No serious adverse effects
Amr et al[43], 2014	N/A	14	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	N/A	Scaffold	Intermediate and chronic (5-84 months, average 23 months)	24	AIS A→B: 2, AIS A→C: 12	Haematoma formation (2), Seroma formation (2)
Suzuki et al[44], 2014	N/A	10	Cervical and thoracic	AIS A: 5, AIS B:5	Autologous iliac bone marrow	BMSC	2.03-8.44 × 108	Intrathecal	Intermediate and chronic (3 wk-12 months)	6	AIS A→B: 1, AIS B→C: 2, AIS B→D: 1; AIS=: 6	No serious adverse effects. Transient anemia after aspiration of bone-marrow cells (2)
Goni et al[45], 2014	N/A	9	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	N/A	Intrathecal	Chronic	24	No significant difference in the ASIA score. Statistically significant differences in the Functional Independence Measure and Modified Ashworth Scale	No serious adverse effects. Postoperative temporary neuropathic pain (2)
El-kheir et al[10], 2014	I/II	50	Cervical (10) and thoracic (40)	AIS A: 15, AIS B: 35	Autologous iliac bone marrow	BMSC	2 × 106/kg	Intrathecal	Chronic (12-36 months, average 18.3 ± 5)	18	AIS A→B: 12, AIS A→C: 4, AIS B→C: 18; AIS=: 16	Temporary mild side effects: Headache, neuropathic pain (30%). No long-term side effects
Mendonca et al[46], 2014	I	14	Thoracic and lumbar	AIS A	Autologous iliac bone marrow	BMSC	5 × 106	Intralesional	Chronic (18-180 months)	6	AIS A→B: 6, AIS A→C: 1; AIS=: 5; Improvements in urologic function (9) and changes in SSEP (1)	One subject developed a postoperatory complication, evolving a cerebrospinal fluid leak that was treated by an additional surgical procedure
Shin et al[47], 2015	I/IIa	19	Cervical	AIS A: 17, AIS B: 2	Human fetal brain	NSC	1 × 108	Intralesional	Acute and intermediate	12	AIS A→C: 2, AIS A→B: 1, AIS B→D: 2; AIS=: 14. Positive response in SSEP (35.3%) and MEP (58.8%) activities of AIS-A patients below the level of injury	No serious adverse effects
Chhabra et al[48], 2016	I/II	7	Thoracic	AIS A, ISCIS total score: 162.6 ± 3.1	Autologous iliac bone marrow	BMSC	3.6 × 108	Intrathecal	Acute	12	ISCIS total score: 134.9 ± 2.5	Liver abscess (1)
Oraee-Yazdani et al[49], 2016	I	6	Cervical (1) and thoracic (5)	AIS A	Autologous iliac bone marrow	BMSC	2 × 106	Intrathecal	Chronic (38.1 ± 15.3 months average)	25-36	AIS A→B: 1. Improvement in sensory level (2), improvement in UDS, especially bladder compliance (1)	No serious adverse effects
Oh et al[32], 2016	III	16	Cervical	AIS B	Autologous iliac bone marrow	BMSC	4.8 × 107	Subdural	Chronic (24-181 months)	6	SEP improvement (4), MEP improvement (6), improvement in motor grade (2)	No serious adverse effects. 8 patients developed mild adverse effects (muscle rigidity, worsened symptoms of tingling sense)
Thakkar et al[33], 2016	N/A	10	Thoracic and lumbar	AIS A	Autologous bone marrow + abdominal adipose tissue	BMSC	1.82 × 108	Intrathecal	Chronic (30-64.8 months)	34	AIS A→B: 6, AIS A→C: 3, AIS A→D: 1	No serious adverse effects
Vaquero et al[27], 2016	I/II	12	Thoracic	AIS A, ASIA score: 165.92 ± 22.83	Autologous bone marrow	BMSC	100 × 106 - 230 × 106	Intralesional	Chronic (38.0-321 months, average 166.3)	12	AIS→B: 3, AIS A→C: 1, ASIA score: 213.25 ± 37.19	22 adverse events of minor (79.1%) or moderate (20.9%) intensity.
Kakabadze et al[25], 2016	I	18	Cervical and thoracic	AIS A: 10, AIS B: 5, AIS C: 3	Autologous iliac bone marrow	BMSC	405-964 × 106	Intrathecal	Intermediate and chronic (max 20 months)	12	ASIA scale improvement by one grade: 7/9 (78%) Improvement by two grades: 2/9 (22%)	No serious adverse effects. Transient fever and headache
Xiao et al[50], 2016	N/A	5	Cervical (1) and thoracic (4)	AIS A	Autologous iliac bone marrow	BMSC	1 × 109	Scaffold	Intermediate and chronic (max 32 months)	12	AIS A No improvement also in MEP and SSEP	No serious adverse effects.
Chhabra et al[51], 2017	I/II	7	Thoracic	AIS A, ISCIS total score: 172.2 ± 2.3	Autologous iliac bone marrow	BMSC	2 × 108	Intralesional	Acute	12	ISCIS total score: 141.7 ± 2.5	Liver abscess (1)
Vaquero et al[52], 2017	II	10	Cervical, thoracic and lumbar	AIS B: 5, AIS C: 5, ASIA total score: 118.2 ±60	Autologous	BMSC	30 × 106 × 4 doses	Intratechal	Chronic (29.2-415.1 months, mean 170.5 ± 118.6)	12	ASIA total score: 235.5 ± 49.35. Motor and sensory scores, bladder, bowel and sexual functions improved. Spasms (2) and neuropathic pain (2) improved	No serious adverse effects. Transient headache and pain in the area of the lumbar puncture
Larocca et al[21], 2017	I/II	5	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	2 × 107	Subcutaneous	Chronic (25-111 months)	6	AIS A→B: 1, AIS A=: 5; One patient improved AIS A→B but reversed at 6 months. Improvements in SCIM III and FIM scale scores	No serious adverse effects
Vaquero et al[20], 2018	II	11	Cervical (4), thoracic (4) and lumbar (3)	AIS A: 3, AIS B: 4, AIS C: 3, AIS D: 1	Autologous	BMSC	100 × 106 × 3 doses	Intrathecal	Chronic (mean 163.8 ± 177.5 months)	10	AIS improvement in 27% of patients. AIS A→B: 1, AIS B→C: 1; AIS C→D: 1	No serious adverse effects. Transitory sciatic pain (37.5%), headaches and pain in the area of lumbar puncture
Guadalajara et al[53], 2018	Case report	1	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	300 × 106 × 3 doses (1/months)	Intrathecal	Chronic	6	Improvement in functionality and especially in Krogh's; Neurogenic Bowel Dysfunction scale	No serious adverse effects
Srivastava et al[54], 2019	I	70	Thoracic and lumbar	AIS A	Autologous iliac bone marrow	BMSC	2,41 ± 1,198 × 106	Intrathecal	Acute and intermediate	12	AIS A→B: 21, AIS A→C: 29, AIS A→D: 5; AIS=: 15	No serious adverse effects
Phedy et al[55], 2019	Case report	1	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	10 − 17 × 106 (× 7 times)	Intrathecal ×1 + Intravenous ×6	Chronic	60	AIS A→C. Increase in AIS score: 10→30. Increase in MRC score for L1 and L2 innervated muscles: 0/5→3/5	No serious adverse effects
Chen et al[56], 2020	I	7	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	> 1 × 109	Scaffold	Acute or intermediate	36	All patients showed significant improvements in the FIM and ADL score. No obvious improvement in the ASIA grade, ASIA motor score, motor function, SSEPs, or MEPs was observed	Stress ulcer and lung infection (1), transient hyperthermia (1), shallow wound (1), spasm (4), paraplegic neuralgia (3), pressure ulcers (1), and lower limb amyotrophy (1)
Sharma et al[57], 2020	N/A	180	Cervical (63), thoracic and lumbar (117)	AIS A: 138, AIS B: 28, AIS C: 10, AIS D: 3	Autologous iliac bone marrow	BMSC	1.06 × 108	Intrathecal	Intermediate or chronic	2-16	FIM and WISCI showed statistically significant improvement	No serious adverse effects
Song et al[58], 2020	N/A	18	Cervical, thoracic and lumbar	ASIA score: 59.75 ± 5.22, SCIM-III score: 40.83 ± 6.58	Autologous iliac bone marrow	BMSC	1 × 107	Intrathecal	N/A	12	ASIA score: 81.1 ± 3.8, SCIM-III score: 72.5 ± 4.3	No serious adverse effects
Oraee-Yazdani et al[36], 2021	I/II	6	Cervical (1) and thoracic (5)	AIS A, SCIM III score: 28.9 ± 13	Autologous iliac bone marrow	BMSC	1 × 106	Intrathecal	Chronic (max 12 months)	30	SCIM III score: 43.1 ± 25.8. Sensory and/or motor improvement was evident in 9 patients according to the AIS assessment	Mild adverse effects: Increase in spasticity, numbness, or tingling sensation, and neuropathic pain
Honmou et al[59], 2021	II	13	Cervical	AIS A: 6, AIS B: 2, AIS C: 5	Autologous	BMSC (auto-serum expanded)	84−150 × 106	Intravenous	Subacute	6	AIS A→B (3/6 patients), A→C (2/6), B→C (1/2), B→D (1/2), C→D (5/5)	No serious adverse effects

Time from injury: Immediate: 0 - 2 h after the injury; acute: Early acute phase: 2 - 48 h; subacute: 2 d - 2 wk; intermediate: 2 wk - 6 months; chronic phase: > 6 months. AIS: American spinal injury association Impairment Scale; ASIA: American Spinal Injury Association; BMSC: Bone Marrow Mesenchymal Stromal Cells; N/A: Not available; NSC: Neural stem cells.

Table 3 Summary of the studies included in the systematic literature review focusing on peripheral blood stem cells (i.e., HSC)

Ref.	Phase of clinical trial	Patients (n)	Localization of injury	Pre-treatment AIS classification or level of injury	Stem cells		Treatment			Follow up (months)	Outcomes
					Origin	Type	Dose	Administration route	Time from Injury		Functional improvement	Adverse effects
Deda et al[60], 2008	N/A	9	Cervical (6) and thoracic (3)	AIS A: 9	Autologous peripheral blood	HSC	5 × 106	Intrathecal	Chronic (6-51 months)	12	AIS A→B: 2, AIS A→C: 7	No serious adverse effects
Hammadi et al[61], 2012	N/A	277	Cervical (69) and thoracic (208)	N/A	Autologous peripheral blood	HSC	1-8 × 108	Intrathecal	Chronic (6-104 months, average 34.5)	24	AIS A→B: 88, AIS A→C: 32, AIS = 157. A subgroup (12 patients) with lesion < 12 months had the best outcome: the percentage improvement reached 50%	No serious adverse effects. Backache and meningism (90%)
Al-Zoubi et al[62], 2014	N/A	19	Thoracic	AIS A	Autologous peripheral blood	HSC	7.6 × 107	Intrathecal	Chronic (12-48 months)	60	AIS A→B: 7. AIS A→C: 2, AIS =: 10	No serious adverse effects
Bryukhovetskiy et al[63], 2015	I/II	202	Cervical (98), thoracic (93) and lumbar (11)	N/A	Autologous peripheral blood	HSC	5.8 × 106	Intrathecal	Chronic (> 12 months)	144	Restoration of neurologic deficit (54.7%); Repair of the urinary system (47.7%). ASIA score improvement in 23 cases	No serious adverse effects

Time from injury: Immediate: 0 - 2 h after the injury; acute: Early acute phase: 2 - 48 h; subacute: 2 d - 2 wk; intermediate: 2 wk - 6 months; chronic phase: > 6 months. AIS: American spinal injury association Impairment Scale; HSC: Hematopoietic stem cells.

Table 4 Summary of the studies included in the systematic literature review focusing on adipose tissue derived stem cells (i.e., ADMSC)

Ref.	Phase of clinical trial	Patients (n)	Localization of injury	Pre-treatment AIS classification or level of injury	Stem cells		Treatment			Follow up (months)	Outcomes
					Origin	Type	Dose	Administration route	Time from injury		Functional improvement	Adverse effects
Hur et al[26], 2016	I	14	Cervical (6), thoracic (7) and lumbar (1)	AIS A: 12, AIS B: 1, AIS D: 1	Autologous subcutaneous fat	ADMSC	9 × 107	Intrathecal	Intermediate and chronic (max 28 months)	8	Improvements in ASIA motor scores (5), voluntary anal contraction (2), ASIA sensory score (10), although degeneration was seen in 1. SSEP median nerve improvement (1)	No serious adverse effects. Transient headache, nausea and vomiting
Tien et al[64], 2019	N/A	31	Thoracic	AIS A, Barthel ADL: 3.35 ± 1.35	Autologous adipose tissue	ADMSC	> 1 × 108	Intrathecal	Acute	12	AIS A→B: 10, AIS A→C: 1, AIS A→D: 2; AIS =: 16 Barthel ADL: 6.48 ± 2.14	No serious adverse effects

Time from injury: Immediate: 0 - 2 h after the injury; acute: Early acute phase: 2 - 48 h; subacute: 2 d - 2 wk; intermediate: 2 wk - 6 months; chronic phase: > 6 months. ADL: Activities of Daily Living; ADMSC: Adipose-derived mesenchymal stem cells; AIS: American spinal injury association Impairment Scale.

Table 5 Summary of the studies included in the systematic literature review focusing on nervous tissue derived stem cells (i.e., NSC, huCNSSC, OEC)

Ref.	Phase of clinical trial	Patients (n)	Localization of injury	Pre-treatment AIS classification or level of injury	Stem cells		Treatment			Follow up (months)	Outcomes
					Origin	Type	Dose	Administration route	Time from injury		Functional improvement	Adverse effects
Shin et al[47], 2015	I/IIa	19	Cervical	AIS A: 17, AIS B: 2	Human fetal brain	NSC	1 × 108	Intralesional	Acute and intermediate	12	AIS A→C: 2, AIS A→B: 1, AIS B→D: 2; AIS=: 14. Positive response in SSEP (35.3%) and MEP (58.8%) activities of AIS-A patients below the level of injury	No serious adverse effects
Ghobrial et al[65], 2017	II	5	Cervical	AIS A: 1, AIS B: 4	Allogeneic fetus	huCNSSC®	15-40 × 106	Intrathecal	Chronic	12	AIS A→B: 1, AIS B→A: 1, AIS=: 3, GRASSP score mean improvement: 14.8 ± 7.8, ISNCSCI score mean improvement: 17.3 ± 16.8	No serious adverse effects
Anderson et al[66], 2017	I	6	Thoracic	N/A	Autologous (sural nerve)	SC	5, 10 or 15 × 106	Intramedullary	Subacute	12	AIS A→B: 1. Improvement in FIM and SCIM III scores	No serious adverse effects
Levi et al[67], 2018	I/II	29	Cervical: 17 (Cohort I: 6, Cohort II: 11) Thoracic: 12	AIS A: 11, AIS B: 18	Allogeneic (Stemcells Inc.)	huCNSSC®	15 − 40 × 106	Intramedullary	Subacute	Up to 56	Improvement in AIS motor scores	15 serious adverse effects in cervical group and 4 in thoracic
Curtis et al[68], 2018	I	4	Thoracic	AIS A	Allogeneic (human-spinal-cord-derived neural stem cell)	NSI-566®	6 injections (Mean number)	Intramedullary	Chronic	60	Improved AIS scores, neurological levels and EMG findings. No improvement in QoL	No serious adverse effects
Levi et al[69], 2019	I/II	17 Cohort I: 6, Cohort II: 11 6/11 monitored	Cervical	AIS A, B	Allogeneic (Stemcells Inc.)	huCNSSC®	15 + 30 + 40 × 106 (Coh.I) 40 × 106 (Coh.II)	Intramedullary	Intermediate or Chronic (max 24 months)	12	Improvement in UEMS score	No serious adverse effects
Curt et al[70], 2020	I/IIa	12	Thoracic	AIS A: 7, AIS B: 5	Allogeneic (Stemcells Inc.)	huCNSSC®	20 × 106	Intramedullary	Intermediate or chronic (max 24 months)	72	Sensory improvements in 5 out of 12 patients. No motor improvements were observed	N No serious adverse effects
Zamani et al[71], 2021	I	3	Thoracic	AIS A	Autologous	OEC+ BMSC	15 × 106, OEC/BMSC = 1/1	Intrathecal	Chronic	24	AIS A→B: 1 and 6 points improvement in SCIM	Mild adverse effects
Gant et al[72], 2022	I	8	Cervical: 4; Thoracic: 4	N/A	Autologous (sural nerve)	SC	50 − 200 × 106	Intramedullary	Chronic	60	The neurological level improved by 1 level in 1 patient. Improvement in Sensory score in all patients with thoracic and in 2 patients with cervical lesion	No serious adverse effects

Time from injury: Immediate: 0 - 2 h after the injury; acute: Early acute phase: 2 - 48 h; subacute: 2 d - 2 wk; intermediate: 2 wk - 6 months; chronic phase: > 6 months. AIS: American spinal injury association Impairment Scale; BMSC: Bone Marrow Mesenchymal Stromal Cells; EMG: Electromyography; MSC; Mesenchimal stem cell; NSC: Neural stem cells; OEC: Olfactory ensheathing cell; SC: Stem cell; SCIM: Spinal cord independence measure.

Table 6 Summary of the studies included in the systematic literature review focusing on nervous tissue derived stem cells (i.e., UCMSC, HUCBC, HESC, WJ-MSC)

Ref.	Phase of clinical trial	Patients (n)	Localization of injury	Pre-treatment AIS classification or level of injury	Stem cells		Treatment			Follow up (months)	Outcomes
					Origin	Type	Dose	Administration route	Time from injury		Functional improvement	Adverse effects
Dai et al[29], 2013	N/A	18	Cervical and thoracic	AIS A: 12, AIS B: 4, AIS C: 2	Allogeneic neonatal umbilical cord tissue	UCMSC	4 × 107	Intralesional	Chronic (18.67 ± 7.6 months)	6	AIS A→B: 7, AIS B→C: 3, AIS=: 8; MEP improvements	No serious adverse effects
Liu et al[73], 2013	N/A	22	Cervical (4), cervical + thoracic (2), thoracic + lumbar (2) and lumbar (7)	Motor function: 58.1 ± 22.2. Algesia: 73.2 ± 25.1. Sensory function: 74.2 ± 26.7. ADL: 29.5 ± 12.5	Allogeneic neonatal umbilical cord tissue	UCMSC	4 × 106/kg	Intrathecal	Intermediate and chronic (2-204 months)	> 12	Motor function: 61.5 ± 23.9. Algesia: 77.2 ± 26.1. Sensory function: 77.3 ± 26.1. ADL: 32.7 ± 12.4	Fever, lumbago, headache, dizziness and other adverse reactions were observed
Cheng et al[74], 2014	N/A	10	Thoracic and lumbar	AIS A, Barthel Index: 33.50 ± 6.69	Allogeneic neonatal umbilical cord tissue	UCMSC	4 × 107	Intralesional	Chronic (12-72 months)	6	Barthel Index: 41.40 ± 6.42; Muscle strength increased. Muscle tension decreased. Increase in maximum bladder capacity and decrease in maximum detrusor pressure	No serious adverse effects
Shroff et al[34], 2016	N/A	226	Cervical and thoracic	AIS A: 153, AIS B: 32, AIS C: 36, AIS D: 5	Pre-implantation stage fertilized ovum	HESC	1.6 × 107 + 1-5 × 1.6 × 107	Intravenous + intralesional	Intermediate and chronic	6-18	AIS A: 98, AIS B: 67, AIS C: 126, AIS D: 9, AIS E: 3	No serious adverse effects. Transient fever and headache
Shroff et al[75], 2017	N/A	15	Cervical and thoracic	AIS A: 13, AIS B: 2	Pre-implantation stage fertilized ovum taken during natural IVF process	HESC	1.6 × 107 + 1-5 × 1,6 × 107	Intravenous + intralesional	Acute, intermediate and chronic (6-15 months)	9	AIS A: 10, AIS B: 2, AIS C: 3	No serious adverse effects
Zhao et al[76], 2017	N/A	8	Cervical (4) and thoracic (4)	AIS A	Allogeneic neonatal umbilical cord tissue	UCMSC	4 × 107	Scaffold	Intermediate and chronic (max 36 months)	12	Expansion of sensation level (62.5%) and expansion of the MEP-responsive area (87.5%) but AIS=	No serious adverse effects
Xiao et al[77], 2018	I	2	Cervical and thoracic	AIS A	Allogeneic	UCMSC+ Scaffold	40 × 106	Intramedullary	Acute	12	AIS A→C in both patients	No serious adverse effects
Deng et al[72], 2020	I	20	Cervical	AIS A	Allogeneic	UCMSC+ Scaffold	40 × 106 (Collagen scaffold)	Intramedullary	Acute	12	AIS A→B (9 patients), AIS A→C (2 patients). Improvement in ADL scores. Improvement in bowel and bladder function	No serious adverse effects
Albu et al[31], 2021	I/IIa	10	Thoracic	AIS A	Allogeneic	WJ-MSC	10 × 106	Intrathecal	Chronic	6	Significant improvement in pinprick sensation in compared with placebo group. No changes in motor function, independence, QoL, SEPs, MEPs, spasticity or bowel function	No serious adverse effects
Yang et al[23], 2021	I/II	102	Cervical, thoracic and lumbar	ASIA score: 158.15 ± 70.93, IANR-SCIFRS total score: 24.54 ± 9.82	Allogeneic neonatal umbilical cord tissue	UCMSC	1 × 106/kg	Intrathecal	Intermediate and chronic (max 240 months)	12	ASIA score: 183.88 ± 69.76, IANR-SCIFRS total score: 29.49 ± 10.47	No serious adverse effects. Fever (14.1%), headache (4.2%), transient increase in muscle tension (1.6%) and dizziness (1.3%)
Zhao et al[78], 2021	N/A	7	Cervical (3) and thoracic (4)	ASIA pin prick: 55.00 ± 28.46, ASIA light touch: 55.00 ± 28.46, ASIA motor score: 42.00 ± 28.19	Allogeneic neonatal umbilical cord tissue	UCMSC	5 × 104	Intrathecal	Intermediate and chronic (max 60 months)	6	ASIA pin prick: 57.06 ± 30.01, ASIA light touch: 58.20 ± 29.36, ASIA motor score: 44.13±27.23	No serious adverse effects
Smirnov et al[16], 2022	I/IIa	10	Cervical, thoracic and lumbar	AIS A: 6, AIS B: 4	Allogeneic	HUCBC	14.8 × 106/kg (Total cell number for 4 infusions)	Intravenous	Acute	12	AIS A→C: 3, AIS B→D: 2, AIS B→E: 2, AIS A→D: 1	No serious adverse effects related to therapy

Time from injury: Immediate: 0 - 2 h after the injury; acute: Early acute phase: 2 - 48 h; subacute: 2 d - 2 wk; intermediate: 2 wk - 6 months; chronic phase: > 6 months. AIS: American spinal injury association Impairment Scale; HESC: Human embryonic stem cells; HUCBC: human umbilical cord blood mononuclear cells; UCMSC: Umbilical cord derived mesenchymal stem cells; WJ-MSC: Wharton's jelly-Mesenchymal stem cells.