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tissue specificity, differentiating into a limited range of cell AECs can be effectively programmed toward the tendon
types within their tissue of origin. 77 lineage, expressing key tenogenic markers, such as SCX and
Tendon stem/progenitor cells have been identified TNMD, 67,92,95,96 particularly when exposed to appropriate
in human and rat tendons, primarily located within the tendon-specific cues or microenvironments. Similarly,
ECM containing biglycan and fibromodulin. TSPCs AMSCs have shown the ability to differentiate into tenocytes
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exhibit multipotent differentiation potential and self- and contribute to tendon repair in preclinical models.
renewal capacity, differentiating into tenocytes, osteocytes, Their accessibility, minimal ethical concerns, and dual
chondrocytes, and adipocytes after in vitro expansion and functionality (tenogenic potential and immunomodulation)
in vivo transplantation, while also forming functional make amniotic-derived cells a valuable addition to the
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extracellular matrices. Compared to tenocytes, TSPCs toolbox for developing immunocompatible and functionally
demonstrate superior proliferative and migratory abilities, robust tendon organoids. 97
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supporting the formation and repair of tendon organoids. Future research should focus on optimizing cell
TSPCs also exhibit high stability and low immunogenicity selection strategies, exploring alternative cell sources, and
in vitro. Notably, aged TSPCs show significant defects in self- integrating gene editing and biomaterial technologies to
renewal and clonogenic potential, resulting in fragile, thin, develop organoid models that more closely mimic native
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and poorly organized tendon organoids with reduced cell tendons. The characteristics of the different cell sources are
density and proliferation. These organoids exhibit inferior presented in Table 2.
structural and functional properties compared to those
formed by young TSPCs. Therefore, young and highly active 4.2. Biochemical factors
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TSPCs should be selected as seed cells for optimal results. The construction of tendon organoids relies on a precisely
MSCs and iPSCs have been widely used in animal studies regulated biochemical microenvironment, which directly
and clinical tendon repair. 81-83 MSCs are multipotent stem influences cell fate determination, matrix synthesis, and
cells capable of self-renewal and differentiation into tissue- tissue function. Biochemical factors primarily include
specific cells in vitro. In addition, their immunomodulatory growth factors, cytokines, and small chemical molecules.
functions and anti-inflammatory properties contribute to These bioactive molecules regulate cell proliferation,
tendon remodeling. MSCs secrete bioactive molecules differentiation, migration, and matrix remodeling during
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and exosomes, such as cytokines, growth factors, and organoid development by activating specific cell fate and
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chemokines, which facilitate tissue construction. Studies developmental signaling pathways. 77,98 Cell signaling
have shown that human umbilical cord MSCs and pathways and intercellular interactions provide essential
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adipose-derived stem cells, 86-88 when combined with support for the development and functional maintenance
appropriate biochemical factors and biomaterials, can be of tendon organoids. Integrating bioactive molecules into
utilized in tendon tissue engineering and serve as materials scaffolds represents a synergistic tissue engineering strategy. 20
for constructing tendon organoids. Differentiating iPSCs Among these biochemical cues, growth factors play
into MSCs and further inducing their differentiation into a critical role in the construction of tendon organoids.
tenocytes can generate functional tendon-like tissues. Insulin-like growth factor 1 (IGF-1) has been identified as
When iPSC-derived MSCs are seeded onto well-aligned a key regulator of collagen synthesis and cell proliferation
ultrafine fibers, they differentiate into tenocyte-like cells in tenocytes. Research has demonstrated that IGF-1
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through the activation of mechanosensitive signaling signaling promotes cell proliferation and protein synthesis
pathways. This process is characterized by increased by activating the phosphoinositide 3-kinase/protein kinase
expression of SCS and COL1, and the production of mature B and extracellular signal-regulated kinase pathways,
collagen. This approach not only addresses limitations thereby supporting normal tendon growth. In addition,
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in cell sourcing but also provides a potential pathway for transforming growth factor-beta (TGF-β) and bone
personalized therapies. morphogenetic proteins are crucial for tendon development
Complementing these sources, amniotic-derived and repair, 100,101 and have been applied to enhance tendon
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cells—encompassing both amniotic epithelial cells graft healing. TGF-β1 102,103 and TGF-β3 88,104 are pivotal
(AECs) and amniotic mesenchymal stromal/stem cells regulators of tendon development and repair, promoting
(AMSCs)—represent another promising cell type for the proliferation and tenogenic differentiation of TSPCs
tendon organoid construction. Derived from the while stimulating the synthesis of collagen and other ECM
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placenta, these cells possess inherent low immunogenicity, components. Members of the fibroblast growth factor
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anti-inflammatory properties, and immunomodulatory (FGF) family, such as FGF2, enhance tenocyte proliferation
capacities, 90,91 akin to MSCs. Both AECs and AMSCs and migration and upregulate the expression of tendon-
exhibit a well-documented potential for tenogenic specific markers, such as SCX and TNDM. 105,106 FGF7 has
differentiation. 67,92-95 Studies have demonstrated that been shown to enhance tenogenesis in human TSPCs through

Volume 1 Issue 3 (2025) 7 doi: 10.36922/OR025170016