Cell-Based Therapies Used to Treat Lumbar Degenerative Disc Disease: A Systematic Review of Animal Studies and Human Clinical Trials

Table 2

Studies assessing the ability of different types of stem cells or progenitor cells to regenerate lumbar intervertebral discs.

Author	Animal model	Degeneration model	Cells transplanted	Method of cell administration	Results/conclusions
Crevensten et al. [38]	Rat	Needle puncture	Allogeneic MSCs	Intradiscal injection of MSCs with 15% hyaluronan gel	MSCs: (i) Trend towards increased disc height; (ii) Retained in disc, remain viable, and can proliferate for at least 28 days
Ganey et al. [39]	Canine	Partial nucleotomy	Non culture expanded autologous adipose derived stem cells	Intradiscal injection with HA	Transplantation of adipose MSCs improved: (i) MRI T2 signal at 12 months; (ii) Disc histology assessment; (iii) Increase collagen II expression
Ghosh et al. [40]	Sheep	Chondroitinase-ABC injection	Allogeneic Stro-3+ Mesenchymal Precursor Cells (MPCs)	Injection with hyaluronic acid (Euflexxa) carrier	MPCs + HA: (i) Restore disc height; (ii) Improved MRI Pfirrmann scores; (iii) Improved histological degeneration scores; (iv) Restoration of extracellular matrix
Hee et al. [41]	Rabbit	Axial loading	Allogeneic bone marrow MSCs	Injection of MSCs combined with axial distraction	(i) MSCs increase disc height and improve histology scores; (ii) MSCs Survive for 8 weeks
Henriksson et al. [42]	Porcine, minipig	Nucleotomy	Xenogeneic Human MSCs	Xenotransplantation of hMSCs with Puramatrix hydrogel carrier or F12 media suspension.	MSCs: (i) Survive in pig disc space for 6 months; (ii) Differentiated into cells representing disc chondrocytes; (iii) Improved MRI appearance in MSC/hydrogel treatment groups; (iv) Combination of with Puramatrix hydrogel increased cell differentiation, matrix production and survival; (v) At three and six months expressed SOX9, aggrecan, and collagen II
Hiyama et al. [43]	Canine	Nucleotomy	Autologous MSCs	Percutaneous injection of MSCs infected with AcGFP1 retrovirus vector.	MSCs: (i) Increased disc height and MRI T2 signal; (ii) Increased production of proteoglycans; (iii) Improved histological structure including AF; (iv) Proportion of FasL-positive cells increased following MSC injection
Ho et al. [44]	Rabbit	Percutaneous needle puncture	Autologous MSCs	Intradiscal injection of BrdU-labelled MSCs	MSCs: (i) Found in disc at 16 weeks post injection; (ii) Discs injected at 6 months post nucleotomy less degenerate than controls but not returned to baseline; (iii) Increased PG in posterior inner annulus; (iv) Did not restore disc height; (v) Only partial arrest possible following administration and more effective at later point of degeneration
Hohaus et al. [30]	Canine	Annular injury and partial nucleotomy	Autologous adipose derived MSCs	Intradiscal injection	Adipose MSCs; (i) Remain viable in disc; (ii) Maintain disc morphology, disc height, and MRI T2 signal; (iii) HA alone insufficient to prevent degeneration
Jeong et al. [45]	Rat	Annular injury	Xenogeneic human MSC	Intradiscal injection	MSCs: (i) Maintain disc height and T2 signal; (ii) Restore AF structure; (iii) Survive for 2 weeks after injection but not 4 weeks
Jeong et al. [46]	Rat	Needle injection	Xenogeneic adipose derived human MSCs	Intradiscal injection	MSCs: (i) Less loss of disc height following injection; (ii) Restore T2 MRI signal; (iii) Restore AF structure; (iv) Upregulate collagen 2 and aggrecan
Miyamoto et al. [47]	Rabbit	NP aspiration	Autologous synovial MSCs	Intradiscal injection	MSCs: (i) Identified in NP at 24 weeks; (ii) Preserve disc height; (iii) Preserve MRI T2 signal for 6 weeks; (iv) Preserve NP histological structure; (v) Increase expression of collagen-II
Murrell et al. [48]	Rat	NP aspiration	Xenogeneic human olfactory neurosphere-derived stem cells	Intradiscal injection	(i) 70% cells identified in discs; (ii) Cells assumed NP cell like phenotype
Omlor et al. [49]	Porcine	Partial nucleotomy	Autologous Bone marrow MSCs	Injection of MSCs transfected with Rv-eGFP within fibrin glue	(i) After 3 days only 9% of injected cells remained in disc
Prologo et al. [50]	Porcine	Needle biopsy of disc	Xenogeneic human MSCs	Xenogenic percutaneous administration of iodine-124 2′-flouro-2′ –deoxy-1B-D-arabinofuranosyl-5-iodouracil –labeled hMSCs	(i) PET-CT confirmed cells in NP on day 0 and day 3 following injection.; (ii) Immunohistological staining at 15 days confirmed presence of cells in treated discs
Sakai et al. [51]	Rabbit	Nucleotomy – NP aspiration.	Autologous MSCs	MSCs embedded in atelocollagen hydrogel	MSCs: (i) Preserved histological structure; (ii) Retained and proliferated in disc; (iii) Increased PGs on histological staining
Sakai et al. [52]	Rabbit	Nucleotomy – NP aspiration.	Autologous bone marrow MSCs	GFP labelled MSC injection	(i) MSCs present in NP at up to 48 weeks; (ii) GFP positive cells expressed collagen II, aggrecan, suggesting site dependent differentiation; (iii) MSCs increased PG content of NP to baseline; (iv) Increased collagen II and aggrecan mRNA, decreased collagen I following MSC injection
Sakai et al. [53]	Rabbit	Nucleotomy – NP aspiration.	Autologous bone marrow MSCs	MSCs embedded in atelocollagen hydrogel	(i) MSCs increased disc height and MRI T2 signal; (ii) MSCs preserve histological structure, including AF; (iii) Restoration of PGs suggested from immunohistochemistry and gene expression
Serigano et al. [54]	Canine	NP Aspiration	Autologous bone marrow MSCs	Intradiscal injection	(i) MSCs significantly increase DHI and MRI T2 signal; (ii) 10^6 and 10^7 cell doses showed improved NP and inner annular histological structure; (iii) 10^5dose group had more degenerative changes; (iv) 10^6 dose group had less apoptosis than 10^5 or 10^7 groups; (v) 10^6 dose group had more live cells at 16 weeks compared to other groups
Sheikh et al. [55]	Rabbit	Needle puncture	Xenogeneic murine ESCs were cultured with cis-retinoic acid, transforming growth factor beta, ascorbic acid, and insulin-like growth factor	Intradiscal injection	(i) Discs treated with ESCs demonstrated increased population of new notochordal cells
Sobajima et al. [56]	Rabbit	Normal discs	Allogeneic MSCs	Injection with MSCs retrovirally transfected with lacZ marker gene.	(i) MSCs detected up to 24 weeks following transplantation.; (ii) No inflammatory response observed in discs following MSC injection; (iii) At 24 weeks more cells located in transition zone and inner AF, taking on more spindle shaped appearance; (iv) Synergism with NPCs and MSCs to increase GAG production, most at 75 : 35 MPC/MSC ratio
Vadalà et al. [57]	Rabbit	Needle Stab	Allogeneic bone marrow MSCs	Intradiscal injection	(i) No evidence of regeneration at 9 weeks on MRI; (ii) X-ray demonstrated osteophyte formation in treated discs; (iii) No cells found in NP using GFP label
Wei et al. [58]	Rat	Nil	Xenogeneic human bone marrow MSCs – CD34− (MSCs) and CD34+ (Haemopoeitic cells) bone marrow cells	Intradiscal injection	(i) CD34− cells (MSCs) remain in NP for 42 days; (ii) CD34+ cells not visible after day 10; (iii) CD34− cells expressed CTO/collagen II or CTO/Sox-9 indicating chondrocytic phenotype differentiation; (iv) No inflammatory cells visible
Yang et al. [59]	Mouse	Annular puncture	Allogeneic bone marrow MSCs	Intradiscal injection	MSCs: (i) Preserve NP and AF structure up to 24 weeks; (ii) Preserve disc height; (iii) PGs upregulated; (iv) Decrease in Col2a1, aggrecan and Sox9 arrested; (v) GAG/DNA increased; (vi) Underwent chondrocytic differentiation; (vii) Increased notochordal cells suggesting MSCs promote NCC survival and proliferation; (viii) Cells survive 24 weeks using GFP labelling
Yang et al. [60]	Rabbit	Needle puncture and nucleotomy	Autologous MSCs	Injection of MSCs with pure fibrinous gelatin-transforming growth factor-beta1 (PFG-TGF-beta1)	(i) MSCs inhibited apoptosis; (ii) MSCs slowed the rate of loss of DHI and increased T2 signal at 12 weeks; (iii) Increased type II collagen in MSC treated group
Zhang et al. [61]	Rabbit	Normal discs	Allogeneic bone marrow MSCs	Injection of LacZ labelled MSCs	(i) MSCs survive in disc; (ii) MSCs increase expression of Type II collagen and PGs

AF: annulus fibrosis, DHI: disc height index, ESCs: embryonic stem cells, GAG: glycosaminoglycan content, GFP: green fluorescent protein, HA: hyaluronic acid, MSCs: mesenchymal stem cells, MPCs: mesenchymal precursor cells, NP: nucleus pulposus, NCC: notochordal cell, NPCs: nucleus pulposus cells, and PG: proteoglycans.