Therapeutic efficacy of intra-articular delivery of encapsulated human mesenchymal stem cells on early stage osteoarthritis

Abstract

Mesenchymal stem cells (MSCs) represent a great therapeutic promise in pre-clinical models of osteoarthritis (OA), but many questions remain as to their therapeutic mechanism of action: engraftment versus paracrine action. Encapsulation of human MSCs (hMSCs) in sodium alginate microspheres allowed for the paracrine signaling properties of these cells to be isolated and studied independently of direct cellular engraftment. The objective of the present study was to quantitatively assess the efficacy of encapsulated hMSCs as a disease-modifying therapeutic for OA, using a medial meniscal tear (MMT) rat model. It was hypothesized that encapsulated hMSCs would have a therapeutic effect, through paracrine-mediated action, on early OA development.Lewis rats underwent MMT surgery to induce OA. 1 d post-surgery, rats received intra-articular injections of encapsulated hMSCs or controls (i.e., saline, empty capsules, non-encapsulated hMSCs). Microstructural changes in the knee joint were quantified using equilibrium partitioning of a ionic contrast agent based micro-computed tomography (EPIC-μCT) at 3 weeks post-surgery, an established time point for early OA.Encapsulated hMSCs significantly attenuated MMT-induced increases in articular cartilage swelling and surface roughness and augmented cartilaginous and mineralized osteophyte volumes.Cellular encapsulation allowed to isolate the hMSC paracrine signaling effects and demonstrated that hMSCs could exert a chondroprotective therapeutic role on early stage OA through paracrine signaling alone. In addition to this chondroprotective role, encapsulated hMSCs augmented the compensatory increases in osteophyte formation. The latter should be taken into strong consideration as many clinical trials using MSCs for OA are currently ongoing.

Biomaterial encapsulation of human mesenchymal stromal cells modulates paracrine signaling response and enhances efficacy for treatment of established osteoarthritis

“…37 Furthermore, in an OA rat model we showed that encapsulated hMSC viability following intra-articular injection was ~ 9 days while nonencapsulated hMSC remained viable for ~ 7 days. 18 We also demonstrated that intra-articular injection of encapsulated hMSCs ameliorated the onset of post traumatic OA. 18 To further explore the utility of this encapsulation system, it was used in the current study to analyze the therapeutic efficacy of encapsulated hMSC in established OA.…”

“…18 We also demonstrated that intra-articular injection of encapsulated hMSCs ameliorated the onset of post traumatic OA. 18 To further explore the utility of this encapsulation system, it was used in the current study to analyze the therapeutic efficacy of encapsulated hMSC in established OA.…”

“…36 In previous work we utilized an alginate microencapsulation system with 1% ultrapure low viscosity sodium alginate crosslinked with BaCl 2 to create microcapsules approximately 150 μ m in diameter. 18,37,38 These studies demonstrated that this encapsulation system permits molecules < 80 kDa to diffuse in and out while preventing the MSCs from integrating with the host tissue. 37 Furthermore, in an OA rat model we showed that encapsulated hMSC viability following intra-articular injection was ~ 9 days while nonencapsulated hMSC remained viable for ~ 7 days.…”

“…16,17 While these cells do have the ability to differentiate into chondrogenic, osteogenic, and adipogenic lineages, there has been increasing interest in the paracrine signaling capabilities of MSCs as a means for their therapeutic effect in OA. [18][19][20][21] MSC secreted factors can create a regenerative niche through numerous mechanisms, including the recruitment of additional stem and progenitor cells along with immunomodulatory effects. MSCs have the capacity to secrete an array of immunosuppressive factors [indoleamine-pyrrole 2,3-dioxygenase(IDO), TNFα-stimulated gene-6(TSG6), nitric oxide (NO), IL-10, galectins, prostaglandin E 2 (PGE2), and transforming growth factor (TGF)-β] to modulate the local inflammatory environment.…”

Alginate-encapsulated brain-derived neurotrophic factor–overexpressing mesenchymal stem cells are a promising drug delivery system for protection of auditory neurons

“…65 Furthermore, there seems to be a strong dependency of the stem cell type and the resulting viability: high viabilities of neural stem cells were observed in alginates, whereas in the same hydrogel system, the viability of dental pulp stem cells decreased over time. 66 Encapsulated bone marrow-derived MSCs with high viability (90% over 21 days) were reported in a study by Westhrin et al 67 Contrary, McKinney et al 68 reported decreasing viabilities of lentivirally modified bone marrow-derived MSCs in alginate (~50% at Day 21).…”