Particle-based artificial three-dimensional stem cell spheroids for revascularization of ischemic diseases

Abstract

Development of new approaches to biomimetically reconstruct vasculature networks remains challenging in regenerative medicine. We introduce a particle-based artificial stem cell spheroid (ASSP) technology that recapitulates paracrine functions of three-dimensional (3D) SSPs for vasculature regeneration. Specifically, we used a facile method to induce the aggregation of stem cells into 3D spheroids, which benefited from hypoxia microenvironment–driven and enhanced secretion of proangiogenic bioactive factors. Furthermore, we artificially reconstructed 3D spheroids (i.e., ASSP) by integration of SSP-secreted factors into micro-/nanoparticles with cell membrane–derived surface coatings. The easily controllable sizes of the ASSP particles provided superior revascularization effects on the ischemic tissues in hindlimb ischemia models through local administration of ASSP microparticles and in myocardial infarction models via the systemic delivery of ASSP nanoparticles. The strategy offers a promising therapeutic option for ischemic tissue regeneration and addresses issues faced by the bottlenecked development in the delivery of stem cell therapies.

Biomimetic Design of Mitochondria‐Targeted Hybrid Nanozymes as Superoxide Scavengers

“…[ 23 ] Our previous studies demonstrated FTn as a promising nanocarrier capable of actively binding with hypoxic cells to provide efficient tissue penetration, predominantly through interactions with its receptor (TfR‐1 in humans; TIM‐2 in mice). [ 24 ] In addition to active targeting of FTn, we previously demonstrated that increased vessel permeability contributed to the improved nanoparticle accumulation in ischemic tissue, [ 25 ] revealing the targeting ability of FTn to be dependent on both active and passive mechanisms.…”

Effects of Mesenchymal Stem Cell‐Derived Paracrine Signals and Their Delivery Strategies

“…For example, MSC spheroids constructed by inducing cell–cell aggregation via supplement of a cell adhesion cue improved MSC survival and retention, and their therapeutic efficacy for treating ischemic diseases, as demonstrated by a 20‐ to 70‐fold upregulation in angiogenic factors VEGF, PDGF, IGF, as well as 1250‐ to 1400‐fold increase in epidermal growth factor (EGF) and angiopoietin‐1(Ang‐1) expression ( Figure ). [ 112 ] Through an alternative approach a hybrid MSC/PEGylated‐DNA nanocomposite spheroid was generated for the treatment of glioblastoma. The MSCs were engineered to express TNF‐related apoptosis‐inducing ligand (TRAIL) while the PEGylated DNA facilitated colloidal stability upon calcium phosphate‐mediated nanoprecipitation and allowed the loading of mitoxantrone, a drug that could sensitize the response of TRAIL in glioblastoma.…”

Therapeutic Biomaterial Approaches to Alleviate Chronic Limb Threatening Ischemia

“…Despite encouraging results, the clinical efficacy is limited by the short half‐life in the pathological environment. [ 3 ] The delivery of pro‐angiogenic growth factors, nucleic acids, and stem or vascular cells [ 6 ] and cell‐free therapies have been the focus of the emerging therapeutic strategies. [ 6,7 ] Many of these non‐traditional strategies have shown their promising effects in pre‐clinical and, in some cases, clinical trials promoting the formation of new blood vessels.…”

“…[ 3 ] The delivery of pro‐angiogenic growth factors, nucleic acids, and stem or vascular cells [ 6 ] and cell‐free therapies have been the focus of the emerging therapeutic strategies. [ 6,7 ] Many of these non‐traditional strategies have shown their promising effects in pre‐clinical and, in some cases, clinical trials promoting the formation of new blood vessels. [ 8 ] However, despite the beneficial outcomes, each of these approaches continue to present several translational challenges and limitations.…”

“…The use of cell‐based therapeutics is an emergent strategy that has promise in the treatment of ischemic diseases. Cell therapies using mesenchymal stem cells, [ 6 ] marrow‐derived CD34+ cells, [ 20 ] mononuclear cells, and endothelial cells have been successful in several preclinical trials. Furthermore, the use of autologous stem cells is drawing attention due to their immuno‐privileged safety profile.…”