Did You Say It Goes IV?

Understanding the Intravenous Stem Cell Administration Route for Osteoarthritis

Osteoarthritis (OA) is now known to be a whole-joint disease involving cartilage, synovium, subchondral bone, and immune cells. Many humans and companion animals are affected with OA in multiple joints, often starting at a relatively young age. Chronic joint inflammation is predominantly macrophage-driven, leading to ongoing pain, cartilage degradation, and disease progression. Although intra-articular (IA) mesenchymal stem/stromal cell (MSC) administration is most common in humans, dogs, and horses intravenous (IV) MSC therapy is being increasingly explored for OA given the systemic immunomodulatory effects of MSCs and their ability to home to inflamed joints.¹

Evidence for IV MSC Homing to Inflamed Joints

Multiple rodent studies have demonstrated that IV-administered MSCs or MSC-derived conditioned media preferentially localize to inflamed joints and periarticular tissues over healthy joints. In mouse and guinea pig arthritis models, systemically delivered MSCs were shown to migrate in response to inflammatory chemokine gradients that are upregulated in arthritic synovium.^2,3

Several studies in dogs, cats, and rodents noted that although long-term MSC engraftment appears minimal, therapeutic effects can be robust, supporting the concept that paracrine (cell-to-cell) signaling  and not structural replacement is the primary mechanism of action for MSCs in OA.^3–7 Collectively, these studies suggest that IV MSCs home transiently to inflamed tissues and exert their effects primarily through immune regulation, and therapeutic benefit may not require high intra-articular cell numbers.^1,8

Immunomodulatory Mechanisms of IV MSC Therapy for OA

A consistent finding across species is the ability of IV MSCs to shift macrophage populations from a pro-inflammatory (M1) phenotype to an anti-inflammatory or tissue-repair (M2) phenotype. In mouse arthritis pain models, IV administration of MSC-conditioned medium significantly reduced mechanical and thermal pain while selectively decreasing M1 macrophages at the site of inflammation, without suppressing total macrophage numbers or beneficial M2 populations.⁴ Depletion of macrophages abolished these analgesic effects, confirming macrophage-dependent mechanisms. MSC-derived factors have been shown to induce synovial M2 macrophages that secrete anti-inflammatory and pro-regenerative mediators. In a mouse OA model, IV delivery of stem cell-conditioned media resulted in reduced synovial inflammation, increased M2 macrophage infiltration, suppression of pro-inflammatory cytokines (IL-1β, TNF-α), and restoration of cartilage and subchondral bone architecture.⁹

Beyond inflammation control, MSC-induced M2 macrophages have been shown to directly influence joint tissue by decreasing chondrocyte expression of catabolic enzymes (MMP-13, iNOS) that break down tissue, increasing anabolic markers (SOX9, aggrecan, collagen II) that support tissue repair, and reducing osteoclast activity and subchondral bone loss.⁹

Improvements Following IV MSC Therapy for OA

Across animal models, IV MSC therapy has been associated with measurable structural benefits including: reduced synovial hyperplasia and inflammatory cell infiltration, improved cartilage staining and lower histologic OA scores, and preservation of subchondral bone volume and trabecular thickness.^1,2,8

In dogs with naturally occurring elbow OA, repeated IV MSC administration resulted in no serious adverse events and significant improvement in owner-reported pain and function scores, however objective gait results were mixed, highlighting the complexity of OA outcome measurement.⁵

A study in cats similarly reported improvements in mobility and comfort following IV MSC therapy, with excellent safety profiles and no evidence of immune rejection or systemic complications.⁶

Studies evaluating IV administered allogeneic uterine-derived MSCs in canine and feline osteoarthritis have also shown promising safety and efficacy results.¹⁰

While further controlled clinical trials are needed, current data support IV MSC therapy as a promising immunomodulatory and potentially disease-modifying approach for osteoarthritis in veterinary medicine.

Taken together, these studies support several key concepts relevant to IV MSC therapy for OA in veterinary patients:

1. Safety profiles are favorable across species, including MSCs harvested from healthy donors from the same (allogeneic) or different (xenogeneic) species
2. IV MSCs do not need to permanently engraft in joints to be effective
3. Immunomodulation (specifically macrophage polarization) is a primary therapeutic mechanism for MSCs in OA
4. Systemic delivery can benefit multiple joints simultaneously, avoiding repeated intra-articular injections. These features make IV MSC therapy particularly attractive for patients with polyarticular disease, advanced OA, or those unable to undergo repeated joint injections.
5. IV administration may be more cost effective in patients with polyarthritis (single IV injection can treat multiple joints)

1.          Beerts C, Broeckx SY, Depuydt E, et al. Low-dose xenogeneic mesenchymal stem cells target canine osteoarthritis through systemic immunomodulation and homing. Arthritis Res Ther. 2023;25(1):1. doi:10.1186/s13075-023-03168-7

2.          Afzali MF, Pannone SC, Martinez RB, et al. Intravenous injection of adipose‐derived mesenchymal stromal cells benefits gait and inflammation in a spontaneous osteoarthritis model. J Orthop Res. 2023;41(4):902-912. doi:10.1002/jor.25431

3.          Dias De Oliveira FB, Antonioli E, Dias OFM, et al. Comparative Effects of Intra-Articular versus Intravenous Mesenchymal Stromal Cells Therapy in a Rat Model of Osteoarthritis by Destabilization of Medial Meniscus. Int J Mol Sci. 2023;24(21):15543. doi:10.3390/ijms242115543

4.          Nemoto W, Yamada K, Shiga R, et al. Therapeutic Potential of Mesenchymal Stem Cell‐Conditioned Medium via Macrophage Subset Regulation in a Mouse Model of Arthritis‐Associated Pain. Eur J Neurosci. 2025;62(8):e70296. doi:10.1111/ejn.70296

5.          Olsen A, Johnson V, Webb T, Santangelo K, Dow S, Duerr F. Evaluation of Intravenously Delivered Allogeneic Mesenchymal Stem Cells for Treatment of Elbow Osteoarthritis in Dogs: A Pilot Study. Vet Comp Orthop Traumatol. 2019;32(03):03. doi:10.1055/s-0039-1678547

6.          Mitani K, Ito Y, Takene Y, Inaba T. Evaluation of the quality of life-enhancing effect of allogeneic feline adipose mesenchymal stem cells in cats with osteoarthritis: A pilot study. Res Vet Sci. 2025;182:105470. doi:10.1016/j.rvsc.2024.105470

7.          Armitage AJ, Miller JM, Sparks TH, Georgiou AE, Reid J. Efficacy of autologous mesenchymal stromal cell treatment for chronic degenerative musculoskeletal conditions in dogs: A retrospective study. Front Vet Sci. 2023;9:1014687. doi:10.3389/fvets.2022.1014687

8.          Beerts C, Pauwelyn G, Depuydt E, et al. Homing of radiolabelled xenogeneic equine peripheral blood-derived MSCs towards a joint lesion in a dog. Front Vet Sci. 2022;9:1035175. doi:10.3389/fvets.2022.1035175

9.          Xia L, Kano F, Hashimoto N, et al. Conditioned Medium From Stem Cells of Human Exfoliated Deciduous Teeth Alleviates Mouse Osteoarthritis by Inducing sFRP1-Expressing M2 Macrophages. Stem Cells Transl Med. 2024;13(4):399-413. doi:10.1093/stcltm/szae006

10. Gallant clinical trial pilot data for feline osteoarthritis (FA-001) and canine osteoarthritis (OA-004)