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Table 2 Functions and applications of stem cells in NEC

From: Stem cells and exosomes: promising candidates for necrotizing enterocolitis therapy

Stem cell type Stem cell origin Stem cell administration Model Modeling methoda Main findings Mechanism Reference
Bone marrow-derived stem cell (BM-MSC)
 BM-MSC Human Intraperitoneal injection In vivo Rat pups with formula feeding, hypoxia-hyperoxia (100% CO2/97% O2, 10 min/5 min, bid for 3 days) and hypothermia (4 °C, 5 min, bid for 3 days) BM-MSCs administrated by intraperitoneal injection improve pathological changes of the neonatal NEC rat model.
BM-MSCs injected rats show significant weight gains and clinical sickness score improvement.
/ [21]
 BM-MSC Mouse homozygotes Intraperitoneal injection
Intravenous injection
In vitro
In vivo
Rat pups with hypoxia (100% N2, 1 min, bid until the end of experiment) and hypothermia (4 °C, 10 min, bid until the end of experiment) BM-MSC proliferation, migration, and survival are increased by HB-EGF.
BM-MSCs administrated intravenously have increased engraftment into intestine compared to BM-MSCs administrated intraperitoneally.
BM-MSCs and HB-EGF co-administration significantly lowers the incidence of NEC and improves gut barrier function as well as survival.
/ [14]
 BM-MSC Human Intravenous injection In vivo Preterm fetal sheep with umbilical cord occlusion (25 min) BM-MSCs administrated intravenously do not relieve hypoxia-ischemia induced adverse intestinal events, which may be associated with NEC. / [22]
 BM-MSC Adult rat Intraperitoneal injection In vivo Rat pups with formula, hypoxia (100% N2, 1.5 min, tid for 4 days) and hypothermia (4 °C, 10 min, tid for 4 days) BM-MSC, AF-MSC, amniotic fluid-derived NSC and enteric NSC treatments all show a significant decrease in intestinal permeability and improved gut barrier function compared to the control group.
There is no significant difference in intestinal permeability or gut barrier function among the four treatment groups.
/ [23]
 BM-MSC Adult rat Intraperitoneal injection In vivo Rat pups with formula, hypoxia (100% N2, 1.5 min, tid for 4 days) and hypothermia (4 °C, 10 min, tid for 4 days) BM-MSC, AF-MSC, amniotic fluid-derived NSC, and enteric NSC treatments all show significant reductions in NEC incidence compared to the control group.
There is no significant difference in incidence among the four treatment groups.
/ [24]
 BM-MSC Adult rat Intraperitoneal injection (conditioned medium) In vitro
In vivo
Rat pups with hyperosmolar formula, hypoxia (5% O2, 95% N2, 10 min, tid for 2 days) and LPS (4 mg/kg, qd for 2 days) Condition medium of PHD2-silenced BM-MSCs repairs the intestinal damage and improves the survival of NEC rats.
BM-MSCs’ paracrine effect is enhanced by PHD-2 silencing.
PHD-2 silencing activates NF-κB and promotes IGF-1 as well as TGF-β2 secretion in BM-MSCs.
PHD2–NF-κB–IGF-1, TGF-β2 [25]
Amniotic fluid-derived mesenchymal stem cell (AF-MSC)
 AF-MSC E14 rat Intraperitoneal injection In vivo Rat pups with hyperosmolar formula, hypoxia (5% O2, 95% N2, 10 min, tid for 2 days) and LPS (4 mg/kg, qd for 2 days) BM-MSCs lack beneficial effects on survival.
AF-MSCs improve survival and increase the repair of injured intestine in NEC via a COX-2 dependent mechanism.
AF-MSCs decrease bowel inflammation, increase cell proliferation and reduce cell apoptosis.
AF-MSCs mediated effects do not depend on direct repopulation, but on a paracrine manner.
Stromal cells expressing COX-2 [26]
 AF-MSC E14 rat Intraperitoneal injection In vivo Rat pups with hyperosmolar formula, hypoxia (5% O2, 95% N2, 10 min, tid for 2 days), and LPS (4 mg/kg, qd for 2 days) AF-MSCs decrease fluid retention and lower the incidence of ascites in NEC rats.   [27]
 AF-MSC E14.5 rat Intraperitoneal injection In vivo Rat pups with formula, hypoxia (100% N2, 1.5 min, tid for 4 days) and hypothermia (4 °C, 10 min, tid for 4 days) BM-MSC, AF-MSC, amniotic fluid-derived NSC and enteric NSC treatments all show significant reductions in NEC incidence compared to the control group.
There is no significant difference in incidence among the four treatment groups.
/ [24]
 AF-MSC E14.5 rat Intraperitoneal injection In vivo Rat pups with formula, hypoxia (100% N2, 1.5 min, tid for 4 days) and hypothermia (4 °C, 10 min, tid for 4 days) BM-MSC, AF-MSC, amniotic fluid-derived NSC, and enteric NSC treatments all show a significant decrease in intestinal permeability and improved gut barrier function compared to the control group.
There is no significant difference in intestinal permeability or gut barrier function among the four treatment groups.
/ [23]
 AF-MSC Mouse pup Intraperitoneal injection In vivo
Ex vivo
Mouse pup with formula, exposure to hypoxia for 4 days and oral LPS injection (4 mg/kg for 2 days) AF-MSC rescues intestinal injury, restores epithelial regeneration, and increases active ISCs. Wnt [28]
Umbilical cord-derived mesenchymal stem cells (UC-MSC)
 UC-MSC Human Intraperitoneal injection In vitro
In vivo
Rat pups with formula gavage (supplemented with 8 mg/kg LPS), hypoxia (5% O2, 95% N2, 10 min, tid), and hypothermia (4 °C, 10 min, bid) UC-MSCs exert beneficial effects in NEC via the production of the paracrine mediator H2S.
UC-MSCs produce more H2S under hypoxic conditions.
H2S [29]
Neural stem cell (NSC)
 NSC Mouse embryos at 12.5 days post coitum Intraperitoneal injection In vivo Rat pups with hypertonic formula, hypoxia (100% N2, 1 min, bid for 3 days), hypothermia (4 °C, 10 min, bid for 3 days), and LPS (2 mg/kg, 8 h after birth) Myenteric plexus ganglia are damaged in NEC patients.
NSC transplantation improves the enteric nervous system, intestinal integrity, stem cell differentiation, and intestinal transit, as well as decreases the mortality of NEC rats.
/ [30]
 NSC E11.5 mouse Intraperitoneal injection In vitro
In vivo
Mouse pups with formula, hypoxia (100% N2, 1 min, bid for 3 days) and hypothermia (4 °C, 10 min, bid for 3 days) NSC transplantation reduces NEC incidence.
NSC injection improves gut barrier function and intestinal motility.
NSC-HB-EGF co-administration or HB-EGF-overexpressed NSC has augmented therapeutic effects on NEC.
/ [31]
 AF-NSC E14.5 rat Intraperitoneal injection In vivo Rat pups with formula, hypoxia (100% N2, 1.5 min, tid for 4 days) and hypothermia (4 °C, 10 min, tid for 4 days) BM-MSC, AF-MSC, amniotic fluid-derived NSC, and enteric NSC treatments all show significant reductions in NEC incidence compared to the control group.
There is no significant difference in incidence among the four treatment groups.
/ [24]
 E-NSC Rat pup
 AF-NSC E14.5 rat Intraperitoneal injection In vivo Rat pups with formula, hypoxia (100% N2, 1.5 min, tid for 4 days) and hypothermia (4 °C, 10 min, tid for 4 days) BM-MSC, AF-MSC, amniotic fluid-derived NSC, and enteric NSC treatments all show a significant decrease in intestinal permeability and improved gut barrier function compared to the control group.
There is no significant difference in intestinal permeability or gut barrier function among the four treatment groups.
/ [23]
 E-NSC Rat pup
 NSC / / In vitro
In vivo
Rat pups with formula, hypoxia (100% N2, 1 min, bid for 4 days) and hypothermia (4 °C, 10 min, bid for 4 days) NSC differentiation in ENC rats is increased by HB-EGF.
NSC expression of nNOS is enhanced by HB-EGF.
/ [32]
  1. aModeling methods for in vivo studies