Temporal changes guided by mesenchymal stem cells on a 3D microgel platform enhance angiogenesis in vivo at a low-cell dose

Abstract

Therapeutic factors secreted by mesenchymal stem cells (MSCs) promote angiogenesis in vivo. However, delivery of MSCs in the absence of a cytoprotective environment offers limited efficacy due to low cell retention, poor graft survival, and the nonmaintenance of a physiologically relevant dose of growth factors at the injury site. The delivery of stem cells on an extracellular matrix (ECM)-based platform alters cell behavior, including migration, proliferation, and paracrine activity, which are essential for angiogenesis. We demonstrate the biophysical and biochemical effects of preconditioning human MSCs (hMSCs) for 96 h on a three-dimensional (3D) ECM-based microgel platform. By altering the macromolecular concentration surrounding cells in the microgels, the proangiogenic phenotype of hMSCs can be tuned in a controlled manner through cell-driven changes in extracellular stiffness and “outside-in” integrin signaling. The softest microgels were tested at a low cell dose (5 × 104 cells) in a preclinical hindlimb ischemia model showing accelerated formation of new blood vessels with a reduced inflammatory response impeding progression of tissue damage. Molecular analysis revealed that several key mediators of angiogenesis were up-regulated in the low-cell-dose microgel group, providing a mechanistic insight of pathways modulated in vivo. Our research adds to current knowledge in cell-encapsulation strategies by highlighting the importance of preconditioning or priming the capacity of biomaterials through cell–material interactions. Obtaining therapeutic efficacy at a low cell dose in the microgel platform is a promising clinical route that would aid faster tissue repair and reperfusion in “no-option” patients suffering from peripheral arterial diseases, such as critical limb ischemia (CLI).

Building Multi-Dimensional Induced Pluripotent Stem Cells-Based Model Platforms to Assess Cardiotoxicity in Cancer Therapies

“…In a biological context, 2D platform offers the least resistance at a single-cell level wherein cellular turnover, metabolism, and protein synthesis occur in an accelerated manner. In contrast, in a 3D tissue-like architecture these processes occur in concert with changes in the local extracellular environment, receiving feedback responses from a multitude of cells that are tightly packed in a small volume ( Baker and Chen, 2012 ; Thomas et al, 2018 ; Thomas et al, 2020 ). With the recent advancements in bioengineering tools, 3D culture systems with varying degrees of complexities have gained significant traction in the field of drug testing and drug discovery ( Figure 2 ).…”

Therapeutic Biomaterial Approaches to Alleviate Chronic Limb Threatening Ischemia

“…[ 86 ] Our laboratory has fabricated a tunable type‐I collagen microgel platform that was able to modulate the paracrine angiogenic action of human mesenchymal stem cells (hMSCs). [ 97 ] The microgels were prepared by crosslinking with 4‐armPEG and optimized by varying polymer concentration, collagen‐crosslinking ratio as well as embedding cell densities. Cells embedded into the microgel were able to induced angiogenesis, ambulation improvement, reduce inflammation and necrosis in a mice model of CLTI.…”

“…Cells embedded into the microgel were able to induced angiogenesis, ambulation improvement, reduce inflammation and necrosis in a mice model of CLTI. [ 97,98 ] A more in‐depth molecular analysis to understand the influence of macromolecular concentration on the paracrine phenotype of hMSCs revealed that the interaction of collagen I with hMSCs’ integrins was crucial in the secretion of pro‐angiogenic mediators. Moreover, collagen microgels significantly improved the performance of similar cell‐delivery platforms with a 20‐fold lower cell dose, as well as allowed to elucidate a mechanism involving pathways modulated in vivo.…”

“…Moreover, collagen microgels significantly improved the performance of similar cell‐delivery platforms with a 20‐fold lower cell dose, as well as allowed to elucidate a mechanism involving pathways modulated in vivo. [ 97 ]…”

Intrinsic Angiogenic Potential and Migration Capacity of Human Mesenchymal Stromal Cells Derived from Menstrual Blood and Bone Marrow

“…In addition, several studies pointed out the beneficial effects of MSC in different disease models, mainly due to the paracrine secretion of pro-angiogenic, anti-apoptotic and anti-inflammatory trophic factors that can contribute to tissue repair [ 20 , 21 , 22 , 23 , 24 , 25 ]. The regenerative potential of MSC is so promising that several groups are already developing delivery methods of MSC on a 3D cell-delivery platform, which can be an alternative to improve cryoprotection, graft survival, angiogenic activity and prolonged cell function in vivo in order to explore the full potential of MSC in regenerative medicine [ 26 ].…”