PMID- 31730488
OWN - NLM
STAT- MEDLINE
DCOM- 20200723
LR  - 20230617
IS  - 1757-6512 (Electronic)
IS  - 1757-6512 (Linking)
VI  - 10
IP  - 1
DP  - 2019 Nov 15
TI  - Intra-pancreatic tissue-derived mesenchymal stromal cells: a promising 
      therapeutic potential with anti-inflammatory and pro-angiogenic profiles.
PG  - 322
LID - 10.1186/s13287-019-1435-2 [doi]
LID - 322
AB  - BACKGROUND: Human pancreata contain many types of cells, such as endocrine 
      islets, acinar, ductal, fat, and mesenchymal stromal cells (MSCs). MSCs are 
      important and shown to have a promising therapeutic potential to treat various 
      disease conditions. METHODS: We investigated intra-pancreatic tissue-derived 
      (IPTD) MSCs isolated from tissue fractions that are routinely discarded during 
      pancreatic islet isolation of human cadaveric donors. Furthermore, whether 
      pro-angiogenic and anti-inflammatory properties of these cells could be enhanced 
      was investigated. RESULTS: IPTD-MSCs were expanded in GMP-compatible CMRL-1066 
      medium supplemented with 5% human platelet lysate (hPL). IPTD-MSCs were found to 
      be highly pure, with > 95% positive for CD90, CD105, and CD73, and negative for 
      CD45, CD34, CD14, and HLA-DR. Immunofluorescence staining of pancreas tissue 
      demonstrated the presence of CD105(+) cells in the vicinity of islets. IPTD-MSCs 
      were capable of differentiation into adipocytes, chondrocytes, and osteoblasts in 
      vitro, underscoring their multipotent features. When these cells were cultured in 
      the presence of a low dose of TNF-alpha, gene expression of tumor necrosis factor 
      alpha-stimulated gene-6 (TSG-6) was significantly increased, compared to control. 
      In contrast, treating cells with dimethyloxallyl glycine (DMOG) (a prolyl 
      4-hydroxylase inhibitor) enhanced mRNA levels of nuclear factor erythroid 
      2-related factor 2 (NRF2) and vascular endothelial growth factor (VEGF). 
      Interestingly, a combination of TNF-alpha and DMOG stimulated the optimal expression 
      of all three genes in IPTD-MSCs. Conditioned medium of IPTD-MSCs treated with a 
      combination of DMOG and TNF-alpha contained higher levels of pro-angiogenic (VEGF, 
      IL-6, and IL-8) compared to controls, promoting angiogenesis of human endothelial 
      cells in vitro. In contrast, levels of MCP-1, a pro-inflammatory cytokine, were 
      reduced in the conditioned medium of IPTD-MSCs treated with a combination of DMOG 
      and TNF-alpha. CONCLUSIONS: The results demonstrate that IPTD-MSCs reside within the 
      pancreas and can be separated as part of a standard islet-isolation protocol. 
      These IPTD-MSCs can be expanded and potentiated ex vivo to enhance their 
      anti-inflammatory and pro-angiogenic profiles. The fact that IPTD-MSCs are 
      generated in a GMP-compatible procedure implicates a direct clinical application.
FAU - Khiatah, Bashar
AU  - Khiatah B
AD  - Department of Translational Research and Cellular Therapeutics, Diabetes and 
      Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 
      E. Duarte Rd, Duarte, CA, 91010, USA.
FAU - Qi, Meirigeng
AU  - Qi M
AD  - Department of Translational Research and Cellular Therapeutics, Diabetes and 
      Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 
      E. Duarte Rd, Duarte, CA, 91010, USA.
FAU - Du, Weiting
AU  - Du W
AD  - Department of Translational Research and Cellular Therapeutics, Diabetes and 
      Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 
      E. Duarte Rd, Duarte, CA, 91010, USA.
FAU - T-Chen, Kuan
AU  - T-Chen K
AD  - Department of Translational Research and Cellular Therapeutics, Diabetes and 
      Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 
      E. Duarte Rd, Duarte, CA, 91010, USA.
FAU - van Megen, Kayleigh M
AU  - van Megen KM
AD  - Department of Diabetes Immunology, Diabetes and Metabolism Research Institute, 
      Beckman Research Institute of City of Hope, Duarte, CA, USA.
FAU - Perez, Rachel G
AU  - Perez RG
AD  - Department of Translational Research and Cellular Therapeutics, Diabetes and 
      Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 
      E. Duarte Rd, Duarte, CA, 91010, USA.
FAU - Isenberg, Jeffrey S
AU  - Isenberg JS
AD  - Department of Translational Research and Cellular Therapeutics, Diabetes and 
      Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 
      E. Duarte Rd, Duarte, CA, 91010, USA.
FAU - Kandeel, Fouad
AU  - Kandeel F
AD  - Department of Translational Research and Cellular Therapeutics, Diabetes and 
      Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 
      E. Duarte Rd, Duarte, CA, 91010, USA.
FAU - Roep, Bart O
AU  - Roep BO
AD  - Department of Diabetes Immunology, Diabetes and Metabolism Research Institute, 
      Beckman Research Institute of City of Hope, Duarte, CA, USA.
FAU - Ku, Hsun Teresa
AU  - Ku HT
AD  - Department of Translational Research and Cellular Therapeutics, Diabetes and 
      Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 
      E. Duarte Rd, Duarte, CA, 91010, USA.
FAU - Al-Abdullah, Ismail H
AU  - Al-Abdullah IH
AUID- ORCID: 0000-0001-7567-0453
AD  - Department of Translational Research and Cellular Therapeutics, Diabetes and 
      Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 
      E. Duarte Rd, Duarte, CA, 91010, USA. IAl-Abdullah@coh.org.
LA  - eng
GR  - R01 DK099734/DK/NIDDK NIH HHS/United States
GR  - R56 DK099734/DK/NIDDK NIH HHS/United States
GR  - U24 DK098085/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20191115
PL  - England
TA  - Stem Cell Res Ther
JT  - Stem cell research & therapy
JID - 101527581
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Biomarkers)
RN  - 0 (Endoglin)
RN  - 0 (Insulin)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (dimethyloxallyl glycine)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Anti-Inflammatory Agents/*metabolism
MH  - Biomarkers/metabolism
MH  - Blood Platelets/metabolism
MH  - Cell Differentiation/drug effects
MH  - Cell Lineage/drug effects
MH  - Cell Membrane/metabolism
MH  - Cell Proliferation/drug effects
MH  - Endoglin/metabolism
MH  - Glycine/analogs & derivatives/pharmacology
MH  - Human Umbilical Vein Endothelial Cells/drug effects/metabolism
MH  - Humans
MH  - Insulin/metabolism
MH  - Male
MH  - *Mesenchymal Stem Cell Transplantation
MH  - Mesenchymal Stem Cells/*cytology/drug effects
MH  - Middle Aged
MH  - *Neovascularization, Physiologic/drug effects
MH  - Pancreas/*cytology
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - Up-Regulation/drug effects
PMC - PMC6858763
OTO - NOTNLM
OT  - Angiogenesis
OT  - Anti-inflammatory
OT  - Mesenchymal stromal cells
OT  - NRF2
OT  - TSG-6
OT  - Type 1 diabetes
OT  - VEGF
COIS- BK, MQ, HTK, and IHA have patents pending related to this study. The other 
      authors declare that they have no competing interests.
EDAT- 2019/11/16 06:00
MHDA- 2020/07/24 06:00
PMCR- 2019/11/15
CRDT- 2019/11/16 06:00
PHST- 2019/04/08 00:00 [received]
PHST- 2019/09/30 00:00 [accepted]
PHST- 2019/09/26 00:00 [revised]
PHST- 2019/11/16 06:00 [entrez]
PHST- 2019/11/16 06:00 [pubmed]
PHST- 2020/07/24 06:00 [medline]
PHST- 2019/11/15 00:00 [pmc-release]
AID - 10.1186/s13287-019-1435-2 [pii]
AID - 1435 [pii]
AID - 10.1186/s13287-019-1435-2 [doi]
PST - epublish
SO  - Stem Cell Res Ther. 2019 Nov 15;10(1):322. doi: 10.1186/s13287-019-1435-2.