Programmable microencapsulation for enhanced mesenchymal stem cell persistence and immunomodulation

Abstract

Mesenchymal stem cell (MSC) therapies demonstrate particular promise in ameliorating diseases of immune dysregulation but are hampered by short in vivo cell persistence and inconsistencies in phenotype. Here, we demonstrate that biomaterial encapsulation into alginate using a microfluidic device could substantially increase in vivo MSC persistence after intravenous (i.v.) injection. A combination of cell cluster formation and subsequent cross-linking with polylysine led to an increase in injected MSC half-life by more than an order of magnitude. These modifications extended persistence even in the presence of innate and adaptive immunity-mediated clearance. Licensing of encapsulated MSCs with inflammatory cytokine pretransplantation increased expression of immunomodulatory-associated genes, and licensed encapsulates promoted repopulation of recipient blood and bone marrow with allogeneic donor cells after sublethal irradiation by a ∼2-fold increase. The ability of microgel encapsulation to sustain MSC survival and increase overall immunomodulatory capacity may be applicable for improving MSC therapies in general.

Shattering barriers toward clinically meaningful MSC therapies

“…This limits the MSC's ability to deliver therapeutic payloads to the host environment via secreted paracrine factors to a short period of time following injection (106,108) and limits cell homing to target tissues (i.e., bone marrow and nervous system). Entrapment of MSCs in the lung capillaries also increases susceptibility to immune clearance (83,108). For example, clinical studies on intravenous administration of radiolabeled MSCs for MI showed a complete lack of MSC homing in the infarcted myocardium following intravascular injection (92,109).…”

“…These results indicate that controlling the cell number inside microgels is an important consideration to achieve the desired residence time of MSCs. Moreover, this improved in vivo residence time of APA-treated MSCs occurred despite the presence of innate and adaptive immune clearance mechanisms, leading to a significant improvement of therapeutic outcome in a bone marrow transplant model (108).…”

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

“…Preconditioning with cytokines such as IFN-γ or TNF-α enhances immunomodulatory factor secretion by MSCs, but such effects have been reported as temporary [69,290]. Alternative tissue engineering approaches including three-dimensional culture and hydrogel encapsulation were employed to enhance MSC functions [291,292]. The therapeutic potentials of MSCs are attributed to complex cellular and molecular mechanisms of action, and such mechanisms still require in-depth exploration for clinical application.…”

Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

“…In some cases, repeated injections over the healing period are required. [ 53 ] Much in the same manner as biomaterials can aid in the retention and therapeutic potential of MSCs delivered by either local [ 10,54 ] or intravenous means, [ 55 ] the use of biomaterials to deliver EVs has emerged as a promising strategy in regenerative medicine to overcome the low retention rates of bolus injections of EVs. Binding to, or encasing EVs in a biomaterial matrix has been shown to extend their bioavailability following delivery, permit sustained and controlled release, maintain stability of EV cargo, and potentially augment therapeutic potency.…”