Table 3.

Biodistribution after IA administration of MSCs in animal models.

Article	Model	Disease (Number of Animals)	Route of Administration (Source of Cells)	Cell-Marking Technique	Detection Time and Outcome	Comments
Khabbal et al. [51] (2015)	Rats	Ischemic stroke model	Intraarterial (external carotid) (allogenic MSCs and xenogenic MSCs—Human MSCs)	MSCs were labeled with 99mTc. Whole body SPECT images and ex vivo radioactivity measures were used to assess biodistribution.	SPECT images were acquired 20 min, 3 h, and 6 h postinjection, after which rats were sacrificed for ex vivo examinations. The majority of the cells were located in the brain and especially in the ipsilateral hemisphere immediately after cell infusion. This was followed by fast disappearance. At the same time, the radioactivity signal increased in the spleen, kidney, and liver.	Human MSCs had faster clearance from the brain than rats MSCs.
Fukuda et al. [56] (2015)	Rats	Ischemic stroke model	Intraarterial (Common carotid artery) (xenogenic MSCs—human MSCs)	Human MSCs were used and labeled with PKH26. Bioluminescence and anti-human vimentin antibodies were used to assess biodistribution of MSCs in ex vivo histological analysis.	Examinations were performed 24 h post infusion. MSCs were widely distributed throughout the cortex and striatum of the ipsilateral hemisphere at 24 h after transplantation of MSCs.
Cerri et al. [52] (2015)	Wistar rats	Parkinson’s disease (unknown number)	Intraarterial. (One group also received mannitol to transiently permeabilize the blood-brain barrier). (allogenic MSCs)	MSCs were double-labelled: CellVue NIR815 Kit for Membrane Labeling (Polyscience, Warrington, PA, http://www.polysciences.com) (accessed on 25 June 2021) and lipophilic red fluorescence dye PKH26. Later histological examinations assessed the distribution of MSCs within the brain.	Necropsies were performed 7 and 28 days after infusion of MSCs. Rats not treated with mannitol showed a very low number of MSCs in the brain at 7 and 28 days post-infusion. Rats treated with mannitol showed a significantly higher number of MSCs within the brain. At day 7, most of MSCs were in the blood vessels, whereas at day 28, most of MSCs were in the parenchyma. Most of MSCs distributed in the same lateral hemisphere where the infusion took place. A strong MSCs signal in the lungs and spleen up to 28 days after infusion was detected.	Authors conclude that the use of a permeabilizing agent is essential to allow passage of MSCs across the blood-brain barrier. A significant number of infused cells accumulated in the peripheral organs (liver, lungs).
Jin et al. [135] (2016)	Beagle dogs	Osteonecrosis of the femoral head	Intraarterial (autogenic MSCs)	MSCs were labeled with 5-bromo-2-deoxyuridin. Histologic examinations (right femoral head, heart, lung, liver, spleen, kidney, gallbladder, small bowel, pancreas, prostate, and testicle) were performed to assess biodistribution.	Histologic examinations were performed 8 weeks after cell infusion. Organs had uneven distribution of MSCs: Heart, liver, gallbladder, kidney and stomach had the major quantity of MSCs.
Arnberg et al. [58] (2016)	Rabbit	Healthy rabbits	Intraarterial infusion (superior mesenteric artery) and intravenous (xenogenic MSCs—Human MSCs)	MSCs were labeled with 11In-oxinate. SPECT-TC images were used to assess biodistribution.	SPECT-TC was performed at 6 h and at 1, 2, and 5 days post infusion. Intravenous administration resulted in early and long distribution of MSCs to the lungs. In contrast, selective intraarterial injections resulted in MSCs distribution in the intestine and in the liver.	Selective intraarterial delivery could improve the results in treating some localized diseases.
Espinosa et al. [59] (2016)	Horses	Healthy horses	Intraarterial selective infusion (median artery) (allogenic MSCs)	MSCs were labeled with 99mTc-HMPAO. Scintigraphic images were taken to assess biodistribution.	Images were taken at the time of injection and at 1, 6, and 24 h postinjection. Homogeneous distribution of radiolabeled MSC was observed through the entire distal limb, including within the hoof. Systemic biodistribution was not assessed.
Sierra-Parraga et al. [57] (2019)	Pigs	Renal ischemia-reperfusion injury. (unknown number).	Intraarterial infusion (renal artery) (allogenic MSCs)	MSCs were labelled with fluorescent compunds. Flow cytometry and genetic tests (PCR) were done in blood and tissues.	Samples were collected 30 min and 8 h after infusion. After infusion, a minor number of MSCs left the kidney through the renal vein, and no MSCs were identified in arterial blood. A low percentage of the infused MSCs were present in the kidney 14 days after administration. Most of MSCs were trapped in the renal cortex.	Renal intra-arterial MSC infusion seem to limit off-target engraftment, leading to efficient MSC delivery to the kidney.
Barthélémy et al. [60] (2020)	Golden Retriever Dogs	Duchenne muscular dystrophy model	Intraarterial (femoral artery) (not stated)	MSCs were labeled with 111In-oxine. Scintigraphy was performed to assess biodistribution.	Scintigraphic images were taken immediately after injection and at 1, 2, 24, 48 h and 1 week. Immediately after injection, MSCs were trapped in the capillary network of the limb and in the lungs. Subsequently, MSCs were also mainly in the injected limb, with a decrease in the lung captation and a relative increase in the liver captation.