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Boosting Vascular Therapies by Modulating the Microenvironment?

Review of “Hyaluronan is Crucial for Stem Cell Differentiation into Smooth Muscle Lineage” from Stem Cells by Stuart P. Atkinson

Current microenvironmental studies now recognize the importance of interactions between stem cells and their niche components to the control of self-renewal and differentiation. Hyaluronan (hyaluronic acid; HA) represents one such component with multiple recognized roles in stem cell biology [1], including a key role in the differentiation of embryonic stem cells (ESCs) toward hematopoietic cells [2].

The laboratory of Qingbo Xu (King's College London BHF Centre, UK) has serious interest in producing smooth muscle cells (SMCs) from ESCs in order to apply them to vascular tissue engineering, angiogenesis, and vasculogenesis. This led them to investigate a potential role for HA in the regulation of SMC differentiation of ESCs. In their new Stem Cells study, they now demonstrate that SMC differentiation requires HA synthesis and pericellular reorganization to boost angiogenic and vasculogenic potential [3]. Could HA modulation represent a new means to create better therapies for the treatment of vascular disease?

By studying the generation of SMCs from ESCs on collagen-IV plates [4], the researchers found a strong increase in HA production and the formation of an HA pericellular “coat” surrounding SMCs. The addition of an HA synthesis inhibitor (4MU) or hyaluronidase (HYAL)-mediated digestion of the coat inhibited SMC differentiation suggesting a vital importance for HA expression and coat formation.

So what controls the production of HA in differentiating ESCs and how does it function? Expression analysis and immunostaining highlighted HAS2 (HA synthase 2) as the likely culprit, with downregulation attenuating SMC differentiation and overexpression enhancing SMC differentiation. Additionally, the addition of various signaling pathway inhibitors demonstrated that HA activated ERK1/2 signaling and suppressed stemness-associated EGFR signaling pathways via an increased in the expression of its principle receptor, CD44.

Finally, the authors employed three experimental models to demonstrate the potential therapeutic applications of this newfound knowledge. Excitingly, the addition of exogenous HA promoted the recellularization of a mouse vessel scaffold in a bioreactor assay and enhanced vasculogenesis in a Matrigel plug model. Perhaps most interestingly of all, HA also boosted SMC accumulation in neointimal lesions of vein grafts in mice.

Overall, the exciting new study points to the construction of the HA microenvironment of the cell as a vitally important step in SMC differentiation from ESCs (See figure for the overall model). The study also highlights HA supplementation or small molecule based HA-based modulation as a potential means to improve treatments for vascular diseases in humans, given the successful in vivo mouse studies.


  1. Solis MA, Chen YH, Wong TY, et al. Hyaluronan regulates cell behavior: a potential niche matrix for stem cells. Biochem Res Int 2012;2012:346972.
  2. Schraufstatter IU, Serobyan N, Loring J, et al. Hyaluronan is required for generation of hematopoietic cells during differentiation of human embryonic stem cells. J Stem Cells 2010;5:9-21.
  3. Simpson RML, Hong X, Wong MM, et al. Hyaluronan Is Crucial for Stem Cell Differentiation into Smooth Muscle Lineage. STEM CELLS 2016;34:1225-1238.
  4. Xiao Q, Zeng L, Zhang Z, et al. Stem cell-derived Sca-1+ progenitors differentiate into smooth muscle cells, which is mediated by collagen IV-integrin alpha1/beta1/alphav and PDGF receptor pathways. Am J Physiol Cell Physiol 2007;292:C342-352.