Tendon stem/progenitor cell ageing: Modulation and rejuvenation

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.