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Figure 1. Structural organization of the tendon microenvironment. The tendon microenvironment is predominantly composed of ECM, constituting
55–70% of its dry weight. This ECM features a hierarchical assembly of type I collagen (97–98% of total collagen), organized from tropocollagen to
microfibrils to fibril bundles, which are reinforced by proteoglycans and glycosaminoglycans to enhance tensile strength and elasticity. Tendon cells
(tenocytes/tenoblasts) are sparsely distributed within the ECM. Vascular and neural networks are predominantly localized to the paratenon, while the
tendon body itself is largely avascular. Created with Adobe Illustrator, Yiwen Xue (2025) https://imgur.la/images/2025/09/09/fig1.jpg.
Abbreviations: COL I: Collagen type I; ECM: Extracellular matrix; IFM: Interfascicular matrix; TSPC: Tendon stem/progenitor cells.
principal cellular populations but are not exhaustive. The intricate; mechanical stimulation of the ECM can modulate
tendon microenvironment, particularly within the IFM, the gene expression profiles of TSPCs, which in turn
also contains a significant complement of resident immune influences the composition and structure of the ECM. 21,24,47
cells, including macrophages, mast cells, lymphocytes, To construct tendon organoids, a comprehensive
neutrophils, and dendritic cells. 37,38 These immune cells are understanding of the structure and microenvironment
increasingly recognized for their crucial roles not only in of tendon tissue is essential. These factors collectively
surveillance and acute inflammatory responses but also in govern tendon development, functional maintenance,
orchestrating tendon repair, remodeling, and modulating and post-injury repair processes. By mimicking the
the local cellular environment. Nerve cells are also present cellular composition, physicochemical properties of the
and contribute to tendon function and injury responses. 39,40 ECM, mechanical environment, and cell-cell interactions
A small population of TSPCs is also present in soft within tendons, it becomes possible to develop functional
connective tissues, capable of forming colonies in vitro. tendon organoids that better replicate native tissue
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Nestin is a neural stem cell marker co-expressed in tendon behavior.
progenitors, and a subpopulation of nestin-positive TSPCs
was identified that exhibits robust tenogenic potential and 3. Organoids
enhanced regenerative capacity. Several other molecular
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markers have been reported to identify TSPCs, including 3.1. Origin and development of organoids
dipeptidyl peptidase-4 (a surface marker linked to Organoids are 3D in vitro tissue analogs derived from adult
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TSPC proliferation), and RSPO2 42,43 (wingless-related stem cells or pluripotent stem cells, capable of mimicking
integration site signaling enhancer promoting tenogenic the structure and function of organs. 48-51 They represent
differentiation). Upon tendon injury, TSPCs can activate, miniature and simplified model systems that exhibit self-
proliferate, and differentiate into tenocytes to promote organization, cellular diversity, and the ability to replicate
tendon healing. Notably, TSPC subpopulations expressing organ functions. 49,50 The concept of organoids dates back
functional markers, such as cathepsin K 44,45 or cytoskeleton to 1907, when Wilson discovered that mechanically
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regulator exhibit distinct roles in ECM remodeling during dissociated sponge cells could reaggregate and self-organize
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repair. The interaction between TSPCs and the ECM is into functional sponge organisms. This groundbreaking

Volume 1 Issue 3 (2025) 4 doi: 10.36922/OR025170016