TABLE 1.
Summary of findings of studies investigating stem cell therapy delivery during ex situ dynamic organ preservation identified after systematic search of the literature (details in Supplementary Material). Results from preliminary studies investigating extracellular vesicle therapy during machine perfusion of transplantable organs are also summarized.
| Studies investigating mesenchymal stromal cell delivery during dynamic organ preservation | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study | Subject | Organ | Organ transplant | Type and duration MP | MSC type | MSC dose | MSC paracrine activity during MP | Device barrier | MSC migration from vascular space | MSC engraftment a | MSC Viability | MSC therapeutic effect | Effect without engraftment |
| [36] | Human | Lungs (discarded) | No | Normothermic, 4 h | Human | 5*106 | NA | NA | NA | NA | NA | ↑ alveolar fluid clearance | NA |
| BM-MSC | |||||||||||||
| [8] | Human | Lungs (discarded) | No | Normothermic, 4 h | MAPc | 107 | NA | NA | NA | NA | NA | ↓ BAL cellularity & histological inflammation | NA |
| [9] | Pig | Lungs | No | Normothermic, max 12 h | Human | 50*106 | NA | Yes, MSC trapped in filters | Yes, some cells in the lumen at histology | Yes,<10 cells/HPF | NA | ↓ IL-8 perfusate concentration | NA |
| UC-MSC | 150*106 | ||||||||||||
| 300*106 | |||||||||||||
| [10] | Rat | Kidneys | No | Hypothermic, 4 h | Rat | 3*106 | NA | NA | Yes | Yes,<10 cells/HPF | NA | ↓ severity histological damage | NA |
| BM-MSC | |||||||||||||
| [37] | Pig | Lungs | No | Normothermic, 6 h | MAPc | 150*106 | No | NA | No | No | NA | No significant therapeutic effect | NA |
| [34] | Mouse | Lungs | No | Normothermic, 1 h | Human | 3*106 | NA | NA | NA | NA | NA | ↑ compliance | NA |
| UC-MSC | ↓ inflammation, neutrophil infiltration & oedema | ||||||||||||
| [38] | Rat | Liver | No | Normothermic, 2 h | Swine | 0.2*106 | NA | NA | NA | NA | NA | No significant therapeutic effect | NA |
| AD-MSC | 106 | ||||||||||||
| [11] | Human | Kidneys (discarded) | No | Sub-normothermic, 24 h | Not specified | 25*106 | Yes | No | No, 95% MSC still circulating at the end of MP | No | NA | ↑ renal cell proliferation & tissue regeneration | Yes |
| 50*106 | |||||||||||||
| 75*106 | |||||||||||||
| 1*108 | |||||||||||||
| 2*108 | |||||||||||||
| [12] | Pig | Kidneys | No | Normothermic, 7 h | Human | 1*105 | NA | Yes, Inhomogeneous distribution in well perfused kidneys | No | No | Disintegrated MSC in colonized glomeruli | Study investigating feasibility and biodistribution | NA |
| AD-MSC & | 1*106 | ||||||||||||
| BM-MSC | 1*107 | ||||||||||||
| [13] | Pig | Lungs | Yes, f-up 4 h | Normothermic, 12 h | Human | 50*106/Kg | Yes | NA | Yes, Unspecified proportion of MSC remained in the lumen | Yes, alveolar interstitium | Yes, indirect evidence based on production of human cytokines | During MP: ↓ apoptosis & perfusate concentration of IL-18 and IFNγ, ↓ peak airways pressure | NA |
| UC-MSC | Post-transplant: ↓ oedema & severity histological injury, f-up limited to 4 h | ||||||||||||
| [14] | Human | Kidneys (discarded) | No | Normothermic, 7 h | MAPc | 50*106 | Yes | No | Yes, Unspecified proportion of MSC kept circulating at the end of MP | Yes, glomeruli in the cortex, peritubular space in the medulla | 21% of circulating MSC were viable | ↑ urinary output & medullar flow | NA |
| ↓ urinary concentration NGAL & perfusate concentration IL-1β | |||||||||||||
| ↑ perfusate concentration IL-10 | |||||||||||||
| [15] | Human | Liver | No | Normothermic, 6 h | MAPc | 50*106 | Yes | Yes, MSC infused via left hepatic vessels did not reach right segments | Yes, only if infused via the hepatic artery | Yes, only if infused via the hepatic artery | NA | ↓ perfusate concentration pro-inflammatory cytokines | Yes |
| ↑ perfusate concentration anti-inflammatory cytokines | |||||||||||||
| [16], [39] | Rat | Liver | No | Normothermic, 8 h | Rat | 1–3*107 | NA | NA | No | No | NA | ↓ perfusate AST/ALT and severity histological damage | Yes |
| BM-MSC | ↓ mitochondrial injury | ||||||||||||
| [17] | Pig | Liver | No | Hypothermic for MSC delivery, 30 min | Human | 5*106 | Yes | Yes, inhomogeneous distribution in well perfused livers | Yes | Yes | Yes, indirect evidence based on production of human cytokines | Study investigating feasibility and biodistribution | NA |
| Normothermic for functional assessment, 4 h | BM-MSC | 1*107 | |||||||||||
| [12] | Pig | Kidneys | No | Normothermic, 7 h | Human | 1*107 | Yes | NA | NA | NA | No significant therapeutic effect | NA | |
| AD-MSC & BM-MSC | |||||||||||||
| [18] b | Pig | Kidneys | Yes, f-up 14 days | Normothermic, 4 h | Human | 1*107 | NA | NA | NA | Yes, Y human chromosome detected in parenchyma but circa 20-fold ↓ 14 days post-transplant | NA | No safety concern during perfusion, No significant post-transplant therapeutic effect | NA |
| AD-MSC | |||||||||||||
| [19] | Rat | Liver | Yes, f-up 14 days | Normothermic, 4 h | Rat | 1*107 | NA | NA | No | No | NA | ↓ post-transplant AST/ALT release & acute cellular rejection | Yes |
| BM-MSC c | |||||||||||||
| [20] | Rat | Liver | No | Normothermic, 6 h | Rat | 1*107 | NA | NA | No | No | NA | ↓ severity of ferroptosis & perfusate AST/ALT concentration | Yes |
| BM-MSC | 3*107 | ||||||||||||
| [21] | Rat | Liver | Yes, f-up 14 days | Normothermic, 4 h | Rat | 1–3*107 | NA | NA | NA | Unspecified location in the hepatic tissue | NA | During MP: ↑ proliferation cholangiocyte extrahepatic bile duct and preservation of epithelial lining | NA |
| BM-MSC c | Post-transplant: ↓ AST/ALT/GGT/bili 7 days post-transplant; ↑ proliferation & ↓ apoptosis peribiliary glands | ||||||||||||
| Studies investigating extracellular vesicles delivery during dynamic organ preservation | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Study | Subject | Organ | Organ transplant | Type and duration MP | Source of EV | EV dose | EV uptake confirmed | EV therapeutic effect | Compared to MSC |
| [22] | Human | Lungs (discarded) | No | Normothermic, 6 h | Human BM-MSC | 100–200 μL | In vitro only (human alveolar epithelial type 2 cell line) | ↑ alveolar fluid clearance & ↓ oedema and weight gain, ↑ compliance | No |
| [10] | Rat | Kidneys | No | Hypothermic, 4 h | Rat BM-MSC | Concentration not reported, EV released by 3*106 cells | NA | ↓ perfusate LDH and MDA, ↑ glucose metabolism,↓ severity histological damage | Yes, magnitude of effects of EV > MSC |
| [34] | Mouse | Lungs | No | Normothermic, 1 h | Human UC-MSC | Concentration not reported, EV released by 3*106 cells | NA | ↑ compliance, ↓ inflammation, neutrophil infiltration & oedema | Yes, magnitude of effects of EV = MSC |
| [23] | Rat | Liver | No | Normothermic, 4 h | Human liver stem-like cells | 5*108 EV/g of liver | Yes, intracellular localization in hepatocytes | ↓ perfusate AST & severity histological damage | No |
| [24] | Rat | Lungs | No | Normothermic, 3 h | Human BM-MSC | 24.56 ± 5.53 *1010 EV/mL, 5 mL were administered | Yes, intracellular localization in alveolar cells | ↓ total vascular resistance, ↑ glucose metabolism and tissue content of ATP | No |
| [25] | Rat | Liver | No | Normothermic, 6 h | Human liver stem-like cells | 5*108 EV/g of liver | Yes, intracellular localization in hepatocytes | ↓ perfusate AST/ALT & ↑ bile excretion, ↓ necrosis & ↑ hepatocellular proliferation | No |
| 25*108 EV/g of liver | |||||||||
| [26] | Human | Kidneys (discarded) | No | Hypothermic, 4 h | Human BM-MSC | 28.5*10^9 | NA | ↓ apoptosis & ↑ tubular cells proliferation, ↓ mitochondrial injury | No |
a
Refers to the visualization of MSC between parenchymal cells (outside of the vascular lining) at histology. When available, the estimated cellular concentration is reported.
b
In this study, porcine kidneys underwent 14 h preservation with hypothermic oxygenated MP, followed by 4 h of normothermic MP with or without MSC infusion.
c
In these studies, MSC were modified to overexpress the enzyme heme oxygenase 1.
Abbreviations: AD-MSC, adipose-derived mesenchymal stem cells; ALT, alanine transaminase; AST, aspartate transaminase; ATP, adenosine triphosphate; BAL, bronchoalveolar lavage; BM-MSC, bone marrow-derived mesenchymal stem cells; EV, extracellular vesicles; HPF, high-power field; IFNγ, interferone gamma; IL-1β, interleukin 1 beta; IL-8, interleukin 8; IL-10, interleukin 10; IL-18, interleukin 18; LDH, lactate dehydrogenase; MAPc, multipotent adult progenitor cells; MDA, malondialdehyde; MP, machine perfusion; NGAL, neutrophil gelatinase-associated lipocalin; UC-MSC, umbilical cord-derived mesenchymal stem cells.
NA, or not applicable, is assigned when a manuscript reported insufficient details for accurate evaluation.