Tendon stem/progenitor cell ageing: Modulation and rejuvenation

Table 1 Recent main factors for regulating tendon stem/progenitor cells biological features

Factor	Cell source	Interventional details	Results	Ref.
PRP	SD rats	10% PRP	10% PRP augments and accelerates the effects of TSPCs on the healing process	[37]
BMACs and PRP complex	Human	A T75 flask (450 μL of BMACs and PRP)	BMAC–PRP enhances the proliferation and migration of TSPCs	[38]
PRP	SD rats	2% PRGF	PRP can activate TSPCs to improve the quality of Achilles tendon rupture healing	[39]
IGF-1, GDF-5 and TGFβ1	Lewis rats	Each growth factor (1, 10, and 100 ng/mL)	GDF-5 promotes TSPCs tenogenic differentiation, and TGFβ1 and IGF-1 increase TSPCs proliferation and are beneficial for phenotype maintenance	[40]
IL-1β	Dogs	-	The expression of inflammatory cytokines is dramatically up-regulated in injured tendon	[41,42]
IL-1β	Mouse	IL-1β (1, 5 or 10 ng/mL)	IL-1β strongly and irreversibly impairs tenogenic and osteogenic differentiation potentials of TSPCs	[43]
IL-6	SD rats	IL-6 (0, 0.1, 1, 10, and 100 ng/mL)	IL-6 enhances proliferation and inhibites tenogenic differentiation in TSPCs via the JAK/Stat3 pathway	[44]
IL-10	SD rats	IL‑10 (0, 0.1, 1, 10 or 100 ng/mL)	IL‑10 enhances cell proliferation and migration, and inhibites tenogenic differentiation in TSPCs	[7]
CTGF	SD rats	CTGF (100 ng/mL)	CTGF plays a role in anti-inflammatory, leading to enhanced tendon healing	[45]
Annexin A1	WT and DF508 mice	-	Decreased annexin A1 expression resulted in elevation of inflammation during the mouse tendon injury process	[46]
Celastrol	Human	celastrol (0, 1, 2, and 4 μM)	Celastrol exerts beneficial effects on human TSPCs stemness and the vital role of the HIF1α-Smad7 pathway in the process is elucidated	[47]
Celecoxib	C57 mouse	celecox (0.1, 1, 10 and 100 ug/mL)	Celecoxib inhibits tenogenic differentiation of TSPCs but has no effects on cell proliferation	[48]
Aspirin	SD rats	Aspirin (1, 2, and 5 mM)	A high concentration of aspirin induces apoptosis in TPSCs by delaying the activation of Wnt/β-catenin pathway	[49]

PRP: Platelet-rich plasma; SD: Sprague–Dawley; TSPCs: Tendon stem/progenitor cells; BMACs: Bone marrow aspirate concentrates; PRGF: Platelet-rich growth factors; CTGF: Connective tissue growth factor; IL-10: Interleukin-10; IL-1β: Interleukin‑1β; TGFβ1: Transforming growth factor-β1; GDF-5: Growth and differentiation factor-5; IGF-1: Insulin-like growth factor1.

Table 2 Age-related markers of tendon stem/progenitor cells

Object	Species model	Groups	Tendon type	Main findings	Ref.
Cell morphology	Human	Y-TSPC group: 28 ± 5 yr; A-TSPC group: 63 ± 14 yr	Achilles tendon	A-TSPC exhibit cell shape of star-like flattened, while Y-TSPCs exhibit spindle-shaped	[14]
	Human	Y-TSPC: 28 ± 5 yr and A-TSPC: 63 ± 14 yr	Achilles tendons	Aged TSPCs are obviously larger in size, have more podia, spread further, and exhibit more robust actin stress fibers, and exhibit higher actin content	[55]
	Rat	old rats: 20 mo and young rats: 8 wk	Achilles tendons	Aged TSPCs display a morphologies of large, flat and heterogeneous morphology, while younger cells exhibit the morphology of uniform elongated	[57]
	Mice	young (2.5, and 5 mo) and aging (9 and 24 mo) mice	Patellar tendons	The number of heterogeneous and cobblestone-shaped TSPCs is dramatically down-regulated with ageing, and the oldest TSPCs have only a few percent displaying the cobblestone shape	[15]
Growth rate	Human	Y-TSPC group: 28 ± 5 yr; A-TSPC group: 63 ± 14 yr	Achilles tendon	A-TSPCs showed a proliferation deficit after 120 d of culture and had an early plateau phase, while Y-TSPCs didn’t exhibit the plateau	[14]
	Rat	3–4 (young) and 24–26 mo (aged)	Patellar tendons	Proliferation rate is decreased and cell cycle progression is delayed with increasing age	[53]
	Rat	three different post-natal stages: 1 d, 7 d and 56 d	Achilles tendon	TSPCs-7d displayed that a higher proliferation rate than the groups of TSPCs-1d and TSPCs-56d	[61]
	Rat	Early P5, mid P10, and late P20 and P30 passages were used	patellar tendons	TSPCs at late P20 and P30 proliferate more rapidly than those at early P5 and mid P10	[62]
Cell clonogenicity	Human	Y-TSPC group: 28 ± 5 yr; A-TSPC group: 63 ± 14 yr	Achilles tendon	Age-dependent clonogenic deficits in TSPCs are based on a decreased in the colony number and CFU efficiency with ageing	[14]
	Human	Group 1: aged 20 (female) and 22 (male); group 2: aged 28 (female) and 31 (male) and Group 3: aged 49 (male) and 50 (female)	Hamstring tendons	The clonogenic potential is dramatically decreased with age; in addition, the size of the colonies was heterogeneous in patients, as the size of colonies produced by cells from aged patients was obviously larger than the colonies composed of cells from younger patients	[50]
	Rat	three different post-natal stages: 1 d, 7 d and 56 d	Achilles tendon	TSPCs-7d have an obviously higher clonogenic ability than TSPCs-1d and TSPCs-56d	[61]
	Rat	early P5, mid P10, and late P20 and P30 passages were used	patellar tendons	The colony numbers of TSPCs increase with passaging,	[62]
Cell migration	Human	Y-TSPC group: 28 ± 5 yr; A-TSPC group: 63 ± 14 yr	Achilles tendon	The migration of TSPCs exhibits a decreasing trend with advanced age	[14]
Cell differentiation	Rat	three different post-natal stages: 1 d, 7 d and 56 d	Achilles tendon	TSPCs from different time groups displays multidifferentiation capability, while the ability of TSPCs-7d is higher than TSPCs-1d and TPSCc-56d, and a similar trend is observed in the tenogenic differentiation capacity	[61]
	Human	Y-TSPC: 25 ± 8yr, and A-TSPC: 65 ± 10 yr	Achilles tendon	Tenogenic differentiation capacity of TSPCs significantly decreases with ageing	[54]
	Mice	young (2.5, and 5 mo) and aging (9 and 24 mo) mice	Patellar tendons	Aged TSPCs formed adipocytes more readily than younger cells and expressed higher levels of adipogenic markers	[15]
	Rat	early P5, mid P10, and late P20 and P30 passages were used	patellar tendons	TSPCs tend to differentiate into osteoblasts, while the adipogenic, chondrogenic and tenogenic differentiation capacities in TSPCs decline during in vitro subculture	[62]
	Mice	early P0, and late P5 passages were used	Achilles tendon	The TSPCs experiences a gradual loss of tenogenic differentiation with passaging due to increased expression and activity of Hdac	[65]
	Human	Y-TSPC group: 28 ± 5 yr; A-TSPC group: 63 ± 14 yr	Achilles tendon	A-TSPC have been reported to display an evident self-renewal and clonogenic decrease, multipotency is maintained in vitro	[14]
	Human	Group 1: aged 20 (female) and 22 (male); group 2: aged 28 (female) and 31 (male) and Group 3: aged 49 (male) and 50 (female)	Hamstring tendons	Multi-potency assays were not influenced by advanced ageing, although Y-TSPCs produced higher levels of some osteogenic and adipogenic genes, while chondrogenic genes were expressed at high levels in A-TSPCs	[50]
CD marker	Rat	3–4 (young) and 24–26 mo (aged)	Patellar tendons	Aged TSPCs express lower levels of CD90.1 than young cells, but higher levels of CD44	[53]
	Rat	early P5, mid P10, and late P20 and P30 passages were used	patellar tendons	CD90 and CD73 is down-regulated with increasing numbers of passaging	[62]
Cell stemness marker	Mice	young (2.5, and 5 mo) and aging (9, and 24 mo) mice	Patellar tendons	The expression of the stem cell markers Oct-4, NS, Sca-1 and SSEA-1 in TSPCs decreased in an age-dependent manner	[15]
Cell viscoelasticity	Rat	old rats: 20 mo and young rats: 8 wk	Achilles tendons	An overall increase in G′, G″and hTSPC with ageing, revealing an important increase in stiffness of aged TSPCs	[57]
	human	Y-TSPC: 28 ± 5 yr and A-TSPC: 63 ± 14 yr	Achilles tendons	Cell stiffness and size increase in A-TSPCs	[55]
Cell senescence markers	human	Y-TSPC group: 28 ± 5 yr A-TSPC group: 63 ± 14 yr	Achilles tendon	A-TSPCs undergo an early appearance of cellular senescence, as determined by quantifying the number of β-gal- positive cells at different time points	[14]
	rat	Early P5, mid P10, and late P20 and P30 passages were used	patellar tendons	The significant up-regulation of β-gal activity in TSPCs with increasing passaging	[62]

Y-TSPC: Young-TSPC; A-TSPC: Aged-TSPCs; TSPCs-7d: TSPCs-7days; P5: Passage 5; CFU: Colony-forming unit; Hdac: Histone deacetylase; CD: Cluster differentiation; NS: Nucleostemin.