The Healing Power of Fat: Adipose-Derived Stem Cells and Tendon Repair

Written by Olivia Woodford-Berry, '19
​Edited by Hannah Ngo, '21

Stem cells, or cells that exhibit the capacity to create other cell types, are a heavily researched topic in the field of regenerative medicine. Unlike organisms like salamanders, humans have very little regenerative ability despite the existence of adult stem cell populations. [1] Such adult stem cell populations are a major research target for tissue engineering, as they lack the controversy that surrounds research using embryonic stem cells. Mesenchymal stem cells (MSCs), a type of stem cell capable of forming fat, bone, tendon, and muscle tissue, is especially promising. [2] Bone marrow- derived mesenchymal stems cells have been thoroughly researched for clinical applications. However, the invasive procedures required to isolate these cells pose limitations for their clinical utility. By comparison, the relative accessibility of adipose-derived mesenchymal stem cells (ASCs), or stem cells derived from fat, have made them an exciting subject for stem cell therapy research. ​

Researchers have established ASCs as a viable alternative to bone marrow-derived mesenchymal stem cells in tissue engineering and confirmed that these cells survive after implantation while exhibiting anti-inflammatory, and anti-cell death effects. [3] While some studies have demonstrated various ways to manipulate ASCs in order form certain types of cells, much research in this field aims to improve the clinical applications of ASC-based therapies. [4] Recently, ASCs were shown to enhance wound healing and regenerate complex structures. To take this one step further, several labs now aim to develop therapies utilizing stem cells and growth factors, which influence stem cell development through biochemical cues. [1] Based on previous research, such treatments could result in better clinical outcomes for difficult to treat tendons or deep tissue injuries. Tendon injuries, especially, are an ideal target for such therapies because they often have poor post-operative functional outcomes due to high prevalence of tissue scar tissue, tendon rupture, and improper healing. These ailments usually result from inflammation and poor tissue regeneration.

​​Shen et al. recently investigated repair outcomes for tendons treated using adipose-derived stem cell sheets and connective tissue growth factor (CTGF). [5] This treatment aimed to balance the documented anti-inflammatory effects of ASCs with the stimulatory effects of CTGF. [6] [7]  CTGF was delivered to the tendon interior via a porous structure (Figure 1), as loading experiments showed that these assemblies release CTGF into the tendon at a constant rate after the first three days post-insertion. Likewise, tendon-specific cell sheets, a scaffold-free, bioengineered cell layer, delivered ASCs isolated from ones own fat to the repaired tendon surface (Figure 2). Overall, prevalence of postoperative complications for control, CTGF, and ASC+ CTGF groups were forty percent, twenty percent, and ten percent, respectively.

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These findings illustrate that ASCs have viable applications beyond wound healing and that combinatorial treatments can improve post-operative functionality of common tendon injuries. The experiments discussed, however, have clear shortcomings. Future research surrounding the long terms effects of this treatment on biomechanical outcomes are necessary. Likewise, these results should be verified in other animal models and eventually in human trials. Still, this study represents a proof of concept for stem cell/ growth factor treatments. While the scope of this paper is small, it alludes to the greater promise of stem cells. Adipose-derived stem cells may help open to the door to making artificial organs and other forms of tissue engineering a reality.

Sources:
[1] Xia H, Li X, Gao W, Fu X, Fang RH, Zhang L, Zhang K. Tissue repair and regeneration with endogenous stem cells. Nature Reviews Materials. 2018 Jun 19:1.

[2] Johal KS, Lees VC, Reid AJ. Adipose-derived stem cells: selecting for translational success. Regenerative medicine. 2015 Jan;10(1):79-96.

[3] Zuk PA, Zhu MI, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue engineering. 2001 Apr 1;7(2):211-28.

[4] Kanthilal M, Darling EM. Characterization of mechanical and regenerative properties of human, adipose stromal cells. Cellular and molecular bioengineering. 2014 Dec 1;7(4):585-97.

[5] Shen H, Jayaram R, Yoneda S, Linderman SW, Sakiyama-Elbert SE, Xia Y, Gelberman RH, Thomopoulos S. The effect of adipose-derived stem cell sheets and CTGF on early flexor tendon healing in a canine model. Scientific reports. 2018 Jul 23;8(1):11078

[6] Shen H, Kormpakis I, Havlioglu N, Linderman SW, Sakiyama-Elbert SE, Erickson IE, Zarembinski T, Silva MJ, Gelberman RH, Thomopoulos S. The effect of mesenchymal stromal cell sheets on the inflammatory stage of flexor tendon healing. Stem cell research & therapy. 2016 Dec;7(1):144.

[7] Lee CH, Shah B, Moioli EK, Mao JJ. CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model. The Journal of clinical investigation. 2010 Sep 1;120(9):3340-9.