MSC Therapy and Secretome — complementary approaches
Rather than competing concepts, MSC therapy and secretome-based approaches represent two complementary strategies within regenerative medicine. Both are built on the same biological foundation — the ability of mesenchymal stromal cells to regulate inflammation and influence the tissue microenvironment — but they differ in how this effect is delivered. Two approaches, one biological principle.
Human na Animals
Biological systems are complex — and no single approach fits all clinical scenarios.Providing access to both MSC-based and secretome-based strategies allows: greater flexibility in treatment planning, adaptation to different disease stages and conditions, better alignment with patient-specific needs
MSC-based therapy
Secretome-based approach
The biology of repair
of allogeneic mesenchymal stromal cells
For many years mesenchymal stromal cells (MSCs) were considered a potential source of replacement cells capable of engrafting within damaged tissues and differentiating into functional tissue-specific elements. However, accumulating experimental and clinical evidence has substantially changed this view. It is now widely accepted that the therapeutic effects of MSCs are mediated predominantly through transient interactions with host cells and the release of a broad repertoire of bioactive molecules, rather than through long-term engraftment or direct tissue replacement (Caplan, 2017; Pittenger et al., 2019).
Systemic effects following intravenous administration
After intravenous administration, most MSCs become temporarily entrapped within the pulmonary microvasculature, where they persist only for a limited period. Despite their short lifespan in vivo, these cells initiate a cascade of immunoregulatory events that can profoundly influence inflammatory processes throughout the organism.
One of the best-characterized mechanisms involves the modulation of macrophage phenotype. Inflammatory tissues are typically enriched with classically activated M1 macrophages, which produce large amounts of pro-inflammatory cytokines and reactive oxygen species. Exposure to MSC-derived mediators, including prostaglandin E2, tumor necrosis factor-inducible gene 6 protein (TSG-6), indoleamine 2,3-dioxygenase (IDO), hepatocyte growth factor and transforming growth factor β, promotes a shift toward alternatively activated M2 macrophages. These cells participate in the clearance of apoptotic debris, secrete anti-inflammatory cytokines such as IL-10 and support tissue remodeling and angiogenesis.
MSCs also affect the adaptive immune response. Numerous studies have demonstrated their ability to suppress proliferation of activated T lymphocytes, impair dendritic cell maturation and promote the expansion of regulatory T cells, thereby restoring immune homeostasis without inducing generalized immunosuppression.
Interestingly, increasing attention has recently been directed toward the fate of administered MSCs themselves. Several reports indicate that a substantial proportion of infused cells undergo apoptosis shortly after administration. Rather than representing a loss of therapeutic activity, apoptosis of MSCs appears to amplify their immunomodulatory effects. Engulfment of apoptotic MSCs by host phagocytes induces production of IL-10, IDO and prostaglandin E2, contributing to the resolution of inflammation. This phenomenon has been referred to as the “dying stem cell hypothesis” and may explain why clinical benefits are frequently observed despite the absence of long-term cell persistence.
Local effects within the joint environment
The mode of action of MSCs following intra-articular administration differs considerably from that observed after systemic delivery. Osteoarthritic joints are characterized by persistent synovial inflammation, increased concentrations of pro-inflammatory cytokines and progressive degradation of the extracellular matrix.
Within this hostile microenvironment MSCs act primarily as local biological regulators. Through secretion of anti-inflammatory cytokines, growth factors and extracellular vesicles, they attenuate synovitis, reduce production of matrix metalloproteinases and stimulate anabolic pathways in resident chondrocytes.
Experimental studies have shown that MSC-derived factors enhance synthesis of aggrecan and collagen type II, while simultaneously inhibiting apoptosis of articular chondrocytes. Although direct incorporation of transplanted cells into newly formed cartilage has occasionally been reported, current evidence suggests that this mechanism contributes only minimally to clinical improvement. Instead, MSCs appear to create conditions that enable endogenous repair processes to occur more efficiently.
Extracellular vesicles released by MSCs are increasingly recognized as important mediators of these effects. They transport regulatory microRNAs, proteins and lipids capable of modulating inflammatory signaling pathways, promoting angiogenesis and supporting tissue regeneration.
Taken together, the contemporary concept of MSC therapy has shifted from a paradigm of cell replacement toward one of transient biological signaling. Rather than becoming part of the repaired tissue, allogeneic MSCs appear to function as short-lived but highly active orchestrators of the regenerative response, facilitating the transition from chronic inflammation toward restoration of tissue homeostasis.
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Implications for Veterinary Medicine and Product Safety
Persistence of therapeutic effects despite transient cell survival
How MSC-mediated biological
changes translate into clinical improvement
From the clinician’s and owner’s perspective, the most important outcome of MSC therapy is the gradual improvement in mobility, comfort and quality of life observed in treated animals. Although these changes may appear straightforward, they result from a complex cascade of biological events occurring within the diseased joint.
Osteoarthritis is not solely a consequence of cartilage wear, but rather a chronic, self-perpetuating inflammatory process involving the synovial membrane, articular cartilage, subchondral bone and periarticular tissues. Elevated concentrations of inflammatory mediators, including IL-1β, TNF-α, prostaglandins and matrix metalloproteinases, sensitize nociceptive nerve endings, contribute to synovial effusion and accelerate degradation of the extracellular matrix. These processes lead to pain, stiffness and progressive functional impairment.
Following intra-articular administration, MSCs act as local biological regulators that help interrupt this pathological cycle. By reducing synovial inflammation, decreasing production of catabolic enzymes and promoting a shift toward a pro-resolving immune environment, MSCs improve the quality of the synovial milieu and decrease activation of pain pathways. In parallel, trophic factors released by MSCs support chondrocyte survival, stimulate matrix synthesis and may contribute to normalization of joint homeostasis.
As a consequence, dogs frequently show improvements that are readily recognized by their owners, including easier rising after rest, increased willingness to exercise, longer walking distances, improved stair climbing ability and a return to previously abandoned activities such as running, playing or jumping into the car. These functional benefits often develop gradually over several weeks, reflecting the time required for resolution of inflammation and restoration of a more favorable intra-articular environment.
Importantly, the observed clinical improvement does not necessarily imply regeneration of damaged cartilage to its original state. Rather, it suggests that MSC therapy can modify the biological processes driving disease progression and pain generation, allowing the joint to function more efficiently despite the presence of structural abnormalities. This distinction may explain why meaningful and sustained improvements in patient well-being can be achieved even in advanced stages of osteoarthritis.