Insights of stem cell-based endogenous repair of intervertebral disc degeneration

Table 2 Highlights and strategy of endogenous repair

Ref.	Cells, biomaterial, and medicine	Highlights and strategy
Human
Liu et al[35], 2016	Amiloride	The biological behavior of NP-MSCs could be inhibited by acidic conditions, and amiloride may meliorate IVD degeneration by improving the activities of NP-MSCs.
Li et al[36], 2017	NP-SCs	NP-SCs keep the regeneration ability similar to BMSCs with superior capacity in chondrogenesis.
Li et al[37], 2018	Modified notochordal cell-rich NP explants	Modified notochordal cell-rich NP explants can attenuate degeneration and senescence of NP-MSC induced by TNF-α.
Jia et al[38], 2017	D-NP-MSCs/ND-NP-MSCs	D-NP-MSCs displayed decreased biological characteristics compared with NP-MSCs.
Wu et al[40], 2017	D-NP-MSCs/UCMSCs	D-NP-MSCs had lower expression of phenotype markers and exhibited reduced proliferation capability and differentiation potentials compared with UCMSCs.
Wang et al[41], 2016	NPSCs/AFSCs/CESCs	A comparison of the osteogenic capacities: CESCs > AFSCs > BM-MSCs > NPSCs; for adipogenesis: BM-MSCs > NPSCs > CESCs > AFSCs; in chondrogenesis: CESCs > AFSCs > BMSCs > NPSCs.
Liang et al[42], 2018	NP-MSCs	The biological behavior of NP-MSCs could be inhibited by compression loading.
Daisuke et al[43], 2012	NPPCs	The frequency of Tie2+ cells decreases markedly in tissue with age and degeneration of the IVD, suggesting exhaustion of their capacity for regeneration.
Chen et al[44], 2018	ICA	The addition of ICA to the conventional freezing medium could improve the viability and function of cryopreserved human NP-MSCs.
Quan et al[48], 2015	MSC-like cells from NP	NP tissue contains MSC-like cells which could be isolated and proliferate in vitro.
Liu et al[49], 2017	AF-MSCs, NP-MSCs, CEP-MSCs	AF-MSCs, NP-MSCs, and CEP-MSCs showed similar multilineage differentiation abilities; CEP-MSCs have the most powerful properties of migration and invasion when compared with AF-MSCs and NP-MSCs.
Blanco et al[27], 2010	NP-MSCs	NP-MSCs were quite similar to BM-MSCs, with the exception that NP-MSCs are not able to differentiate into adipocytes.
Lazzarini et al[50], 2018	NP-MSCs	NP-MSCs have the capacity of neuronal differentiation and could express neural markers without any electric functional properties.
Pereira et al[51], 2016	CEP-MSCs	MSCs from CEP promote IVD regeneration by remodeling ECM.
Qi et al[57], 2018	MSC-CM	MSC-CM has potential to alleviate HG induced cell cycle arrest and ECM degradation of NP-MSCs via p38 MAPK pathway.
Li et al[64], 2018	CsA	CsA efficiently inhibited compression-induced NP-MSCs apoptosis by alleviating mitochondrial dysfunction and oxidative stress.
Rat
Zhao et al[34], 2017	NP-MSCs	The efficacy of NP-MSCs is compromised by age, and old NP-MSCs displayed senescent features.
Li et al[39], 2019	NP-MSCs	The MSC-CM + CC method (MSC complete medium culture + cloning cylinder) is a more reliable and efficient way for isolating and purifying NP-MSCs.
Li et al[45], 2013	NP-MSCs	Compared to AD-MSCs, NP-MSCs showed greater viability, proliferation, and chondrocytic differentiation under hypoxia.
Wang et al[46], 2019	Injectable hydrogel-loaded NP-MSCs	Injectable hydrogel-loaded NP-MSCs transplantation can delay the level of IVD degeneration and promote the regeneration of the degenerative IVD in a rat model.
Nan et al[52], 2019	Nar	Nar efficiently attenuated H2O2-induced NP-MSCs apoptosis and mitochondrial dysfunction through PI3/AKT pathway.
Han et al[29], 2014	NP-MSCs	An acidic environment is a major obstacle for IVD regeneration by AD-MSCs or NP-MSCs; NP-MSCs appeared less sensitive to inhibition by acidic PH.
Tao et al[28], 2013	NPCs-NP-MSCs co-culture	NP-MSCs could tolerate IVD-like high osmolarity and NPCs-NP-MSCs co-culture increased cell proliferation and the expression of SOX-9, aggrecan, and collagen-II.
Tao et al[53], 2015	TGF-β3/IGF-1	The synergy between TGF-β3 and IGF-1 enhanced NP-MSCs viability, ECM biosynthesis, and differentiation towards NPCs by activating the MAPK/ERK signaling pathway.
Liu et al[30], 2019	N-NP-MSCs/D-NP-MSCs	N-NP-MSCs showed a significantly higher proliferation rate, better stemness maintenance ability, but reduced cell apoptosis rate compared with D-NP-MSCs.
Li et al[55], 2018	NP-MSCs	Hyperosmolarity of the IVD significantly inhibited the proliferation and chondrogenic differentiation of NP-MSCs by activating the ERK pathway.
Cheng et al[56], 2019	TNF-α	Treatment with a high concentration of TNF-α (50-200 ng/mL) could induce apoptosis of NP-MSCs, whereas a relatively low TNF-α concentration (0.1-10 ng/mL) promoted the proliferation and migration of NP-MSCs, but inhibited their differentiation toward NP cells.
Lin et al[58], 2017	L-PD of NP-MSCs	NP-MSCs at a L-PD (5 cells/cm2) have better biological characteristic, stronger multilineage differentiation, and higher expression of stem cell biomarkers compared with those at an M-PD (100 cells/cm2) and H-PD (10000 cells/cm2).
Yang et al[65], 2009	BMSCs	BMSCs could arrest the degeneration of the murine notochordal NP and contribute to the augmentation of the ECM in the NP by both autonomous differentiation and stimulatory action on endogenous cells.
Liu et al[68], 2019	NP-MSCs	High glucose concentration significantly decrease vitality, migration, and stemness of NP-MSCs.
Zhang et al[69], 2015	NP-MSCs	The chondrogenic ability of NP-MSCs and BM-MSCs was similar under induction in vitro.
Dog
Erwin et al[47], 2013	NPPCs	NPPCs have higher expression of the Nanog gene compared to MSCs and are capable of differentiation along chondrogenic, adipogenic, and neurogenic lineages in vitro and into oligodendrocyte, neuron, and astroglial specific precursor cells in vivo in the myelin-deficient shiverer mouse.
Bovine
Tekari et al[63], 2016	NPPCs	The Tie2+ cells (NPPC) were spheroid in shape with capacity of multi-differentiation and may decline fast, which was partially reversed by FGF2 and hypoxic conditions.
Rabbit
Jia et al[54], 2018	P-PRP/L-PRP	Both P-PRP and L-PRP could induce the proliferation and NP-differentiation of NP-MSCs; P-PRP could reduce the inflammatory and catabolic responses by avoiding the activation of the NF-κB pathway.
Rhesus macaque
Huang et al[66], 2013	DPCs, SLRP	SLRP could reduce the susceptibility of DPCs to hypoxia-induced apoptosis via promoting the activation/stabilization of HIF-1α and HIF-2α.

MSC: Mesenchymal stem cell; IVD: Intervertebral disc; NP: Nucleus pulposus; AF: Annulus fibrosus; CEP: Cartilaginous endplates; UCMSCs: Umbilical cord MSCs; AD: Adipose tissue; ECM: Extracellular matrix; ICA: Icariin; CM: Conditioned medium; HG: High glucose; CsA: Cyclosporine; Nar: Naringin; TGF-β3: Transforming growth factor beta 3; IGF: Insulin-like growth factor; TNF: Tumor necrosis factor; L-PD: Low plating density; NPPC: NP-derived progenitor cell; BM-MSC: Bone marrow mesenchymal stem cell; P-PRP: Pure platelet-rich plasma; L-PRP: Leukocyte-containing platelet-rich plasma; DPCs: Intervertebral disc progenitor cells; SLRP: Leucine-rich proteoglycans.