Table 4 Immunomodulatory function of hAECs in different diseases

Ischemic stroke

Tail vein injection (1 × 10⁶ hAECs); saphenous vein injection (5 × 10⁶ hAECs)

Mice, marmosets

Reducing brain infarcted volume and functional deficits; promoting long-term functional recovery

Inhibiting apoptosis and inflammation; modulating immunosuppression

[70]

Intracerebral hemorrhage

Injection of cortex (1 × 10⁶ hAECs)

Rats

Reducing brain edema; ameliorating the neurologic deficits

Suppressing the activation of microglia; reducing the inflammatory response

[101]

Perinatal brain injury

Intravenously (1 × 10⁵ hAECs)

Mice

Reducing microglia apoptosis; increasing microglial phagocytic activity

Modulating microglia via releasing trophic factors

[102]

Fetal brain injury

Injection of brachial artery catheter (6 × 10⁶ hAECs)

Ewes

Reducing white matter injury; mitigating associated brain injury

Inhibiting inflammation and apoptosis; reducing the number of activated microglial cells

[103, 104]

Multiple sclerosis

Intravenously (2 × 10⁶ hAECs)

Mice

Reducing monocyte/macrophage infiltration and demyelination

Mediating immunosuppression via secreting TGF-β and PGE2; promoting Th2 cytokine shift

[105]

Lung injury

Intraperitoneally (4 × 10⁶ hAECs)

Mice

Decreasing neutrophil infiltration, fibrosis, collagen content; repairing lung function

Depending on the function of host macrophage

[106]

Lung injury

Intraperitoneally (4 × 10⁶ hAECs)

Mice

Reducing macrophage infiltration; increasing the number of M2 macrophage

Modulating macrophage polarization, migration, and phagocytosis via paracrine pathway

[107]

Lung injury

Intraperitoneally (4 × 10⁶ hAECs)

Mice

Mitigating lung inflammation and fibrosis

Tregs are required for hAEC-mediated macrophage polarization

[108]

Lung injury

Intraperitoneally (4 × 10⁶ hAECs)

Mice

Reducing pro-inflammatory immune cells; preventing lung injury

Mediating immunomodulation partly though LXA4

[109]

Preterm neonatal lung injury

Intratracheally (90 × 10⁶ hAECs)

Lambs

Modulating the pulmonary inflammatory response to ventilation; reducing acute lung injury

Immunomodulatory effects

[110]

Fetal lung injury

Fetal jugular vein injection (90 × 10⁶ hAECs); fetal intratracheal infusion (18 × 10⁶ hAECs)

Sheep

Attenuating the fetal pulmonary inflammatory response

Reducing inflammatory cytokines

[111]

Neonatal lung injury

Intraperitoneally (4.5 × 10⁶ hAECs)

Mice

Partially reducing hyperoxia-induced inflammation and structural lung damage

Attenuating inflammation

[112]

Neonatal lung injury

Intravenously; intratracheal infusion (5 × 10⁴; 7.5 × 10⁴; 1 × 10⁵ hAECs)

Mice

Improving the tissue-to-airspace ratio and the long-term of cardiorespiratory function

Reducing macrophages, dendritic cells, and natural killer cells

[113]

Achilles tendon injury

In situ filling (10 × 10⁶ hAECs)

Sheep

Inhibiting inflammatory cell infiltration; activating the M2 macrophage subpopulation

Regulating inflammatory and immunomodulatory response; accelerating blood vessel and ECM remodeling

[68]

Autoimmune ovarian disease

Intravenously (2 × 10⁶ hAECs)

Mice

Restoring ovarian function; upregulating Treg cells; reducing the inflammatory reaction

Modulating macrophage function by paracrine factors (TGF-β and MIF)

[114]

Experimental autoimmune thyroiditis; systemic lupus erythematosus

Intravenously (1.5 × 10⁶ hAECs); intravenously (1.5 × 10⁶ hAECs)

Mice

Preventing lymphocyte infiltration into the thyroid; improving the damage of thyroid follicular; reducing immunoglobulin profiles

Modulating the immune cell balance by downregulating the ratios of Th17/Treg cells; upregulating the proportion of B10 cells

[115]

Diabetic wound healing

Intradermally (1 × 10⁶ hAECs)

Mice

Promoting diabetic wound healing

Reducing inflammation and promoting neovascularization by paracrine pathway

[116]

Liver injury

Intravenously (2 × 10⁶ hAECs)

Mice

Reducing hepatic fibrosis

Inducing M2 macrophage phenotype

[117]