Current Status of Angiogenic Cell Therapy and Related Strategies Applied in Critical Limb Ischemia
Abstract
:1. Critical Limb Ischemia
2. Animal Models of CLI
Strategies Followed to Assess Neovascularization in CLI
3. Angiogenic Cell Therapy
3.1. Cell Therapies Based on Single or Combined Isolated Cells
3.2. Cell Therapies Based on Cellular Cocktails
4. Clinical Trials
Limitations in Cell-based Clinical Trials
5. Strategies Derived from Cell Therapy
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
a | Autologous |
ABI | Ankle brachial index |
aBMCs | Autologous bone marrow cell transplantation |
AD | Arteriolar density |
ADRCs | Adipose-derived regenerative cells |
AFS | Amputation free survival |
AFSCs | Amniotic fluid-derived stem cells |
AI | Angiographic index |
AR | Amputation rate |
ASCs | Adipose tissue derived stem cells |
ASO | Atherosclerosis obliterans |
BM-MNCs | Bone marrow-derived mononuclear cells |
BM-MSCs | Bone marrow mesenchymal stem cells |
BM-TNCs | Bone marrow total nucleated cells |
BFP | Blood flow perfusion |
CACs | Circulating angiogenic cells |
CBF | Calf blood pressure |
CD | Capillary density |
CM | Conditioned medium |
CLI | Critical limb ischemia |
CVDs | Cardiovascular diseases |
CVF | Collateral vessel formation |
DM | Diabetes mellitus |
DR | Death rate |
ECFCs | Endothelial colony forming cells |
ECs | Endothelial cells |
ECEPCs | Enriched circulating endothelial progenitor cells |
EPCs | Endothelial progenitor cells |
ESC-ECP | Stem cell-derived endothelial cell product |
FAL | Femoral artery ligation |
FGF1 | Fibroblast growth factor 1 |
FS | Functional score |
G-CSF | Granulocyte colony-stimulating factor |
HD | High dose |
HGF | Hepatocyte growth factor |
HIF-1a | Hypoxia-inducible factor 1-alpha |
HPCs | Hematopoietic progenitor cells |
h | Human |
IA | Intraarterial |
IC | Intracardiac |
IHC | Immunohistochemistry |
IM | Intramuscular |
IV | Intravenous |
LD | Low dose |
LDP | Laser Doppler Perfusion |
MACs | Myeloid angioenic cells |
MD | Medium dose |
MMPs | Matrix metalloproteinases |
MP | Matrigel plug |
MSCs | Mesenchymal stem cells |
NC | Non-controlled |
NO | Nitric oxide |
NR | Non-randomized |
PAD | Peripheral arterial disease |
PB-MNCs | Peripheral blood mononuclear cells |
PFWD | Pain-free walking distance |
PRP | Platelet-rich plasma |
RCT | Randomized controlled trial |
RPS | Rest pain score |
SC | Subcutaneous |
SMCs | Smooth muscle cells |
SMPCs | Smooth muscle progenitor cells |
SVF | Stromal vascular fraction |
TAO | Thrombo-angiitis obliterans |
TcPO2 | Transcutaneous oxygen pressure |
TR | Tissue regeneration |
UH | Ulcer healing |
VAS | Visual analogue scale |
VD | Vessel diameter |
VEGF | Vascular endothelial growth factor |
VIP | Vascular intersection percentage |
VS | Visual Scale |
VSEL | Very small embryonic-like stem cells |
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Cell Type | Author (Year) | Ref. | Cell Source | Animal (Strain) | Administration (×105 Cells) | Route of Administration | Follow-up (Weeks) | Outcome |
---|---|---|---|---|---|---|---|---|
aMSCs | Cunha (2013) | [69] | Bone marrow | Mice (Balb-C & C57/BL6) | 5 | IM | 4 | VS, CD, TR |
hMSCs | García-Vazquez (2019) | [70] | Adipose tissue | Mice (Athymic nude) | 6 | IM | 3 | BFP, CD, VS |
aMSCs | Nammian (2021) | [71] | Bone marrow & adipose tissue | Mice (C57/BL6) | 5 | IM | 4 | FS, CD |
hMSCs + hECFCs | Rossi (2017) | [72] | Bone marrow & peripheral blood | Mice (Athymic nude) | N/A | IV | 2 | BFP, CD, VS |
hCD34+ | Lian (2018) | [73] | Peripheral blood | Mice (Balb-C Nude) | 1 | IM | 3 | FS, VS |
hEPCs | Kalka (2000) | [74] | Peripheral blood | Mice (Athymic nude) | 5 | IC | 4 | BFP, CD, VS |
hEPCs | Urbich (2003) | [75] | Peripheral blood | Mice (Athymic NMRI Nude) | 5 | IV | 2 | BFP, CD |
hEPCs | Zhao (2016) | [76] | Fetal aorta | Rat (Goto-Kakizaki) | 100 | IM | 8 | BFP, CD, VS |
hCACs | Beltrán-Camacho (2020) | [47] | Peripheral blood | Mice (Balb-C Nude) | 5 | IM | 4 days | BFP, CD, FS, VD |
hEPCs + hOECs | Yoon (2005) | [77] | Peripheral blood | Mice (Athymic nude) | 2 | IM | 3 | BFP, CD, VS, MP |
hEPCs + hSMPCs | Foubert (2008) | [78] | Umbilical cord blood | Mice (Athymic nude) | 5 | IV | 2 | BFP, CD, AD |
hESC-ECP | MacAskill (2018) | [40] | hESC line | Mice (CD1-STZ DM inductor) | 10 | IM | 3 | BFP, CD |
aBM-MNCs | Shintani (2001) | [79] | Bone marrow | Rabbit (Male New Zealand White) | 5 | IM | 4 | BFP, CBP, CD, CVF |
aBMCs | De Nigris (2007) | [80] | Bone marrow | Mice (ApoE−/−) | 20 | IV | 2 | BFP, CD, CVF |
aBM-MNCs | Jeon (2007) | [81] | Bone marrow | Mice (C57/BL6) | 20 | IM | 4 | CD, CVF |
aBM-MNCs | Gan (2009) | [82] | Bone marrow | Mice (C57/BL6) | 30 | IM | 2 | BFP, CD |
hBM-NCs | Liu (2009) | [83] | Bone marrow | Mice (C57/BL6 ApoE−/−) | 250 | IA | 4 | BFP, CVF |
aBM-MNCs | Brenes (2012) | [84] | Bone marrow | Mice (C57/BL6) | 5, 10 & 20 | IM | 4 | BFP, CD, FS |
aBM-MNCs | Reis (2014) | [85] | Bone marrow | Mice (Balb-C) | 5 | IM | 4 | CD, TR, VS |
hBM-MNCs | Rojas-Torres (2020) | [41] | Bone marrow | Mice (Balb-C Nude) | 10 | IM | 3 | BFP, CD, FS, VD |
aBMC-derived macrophages | Kuwahara (2014) | [86] | Bone marrow | Mice (C57/BL6N) | 1 | IM | 4 | BFP, CD |
hALDH high activity cells | Capoccia (2009) | [87] | Bone marrow | Mice (NOD/SCID b2M) | 1–2 | IM | 3 | BFP, CD |
aMIAMI cells | Rahnemai-Azar (2011) | [88] | Bone marrow | Mice (Balb-C) | 10 | IM | 4 | BFP, CD, FS, VS |
hPB-MNCs1 | Li (2006) | [89] | Peripheral blood | Mice (Athymic nude) | 10 | IM | 4 | BFP, AI, CD, VS |
aPB-MNCs + PRP | Padilla (2020) | [90] | Peripheral blood | Rat (Wistar) | 15 | IM | 4 | AI, VIP |
aASCs | Liu (2020) | [91] | Adipose tissue | Mice (C57/BL6) | 10 | IM | 3 | BFP, CD, VS |
aASCs + macrophages | Rybalko (2017) | [92] | Adipose tissue | Mice (C57/BL6) | 2 | IM | 3 | BFP, CD |
hSVF | Jin (2017) | [93] | Adipose tissue | Mice (Nude) | 10 | IM | 2 | BFP, VS, CD, MP |
PDX-PAD (adherent stromal cells) | Prather (2009) | [94] | Placenta | Mice (Balb-C) | 10 | IM | 3 | BFP, CD, FS |
PLX-PAD (MSC like stromal cells) | Zahavi-Goldstein (2017) | [95] | Placenta | Mice (C57/BL6) | 0.02–10 | IM & SC | 3 | BFP, VS |
Author (year) | Ref. | Type of Cell Therapy | Type of Study | Cause of PAD/CLI | Disease Stage | Nº Patients (T/C) | Control | Administration (x106 cells) | Route of Administration | Follow-up (Months) | Outcome |
---|---|---|---|---|---|---|---|---|---|---|---|
Huang (2005) | [125] | PB-MNCs1 | RCT | ASO | Fontaine III–IV | 28 (14/14) | Blank | 3000 | IM | 3 | ABI, AR, DR, PFWD, RPS, UH |
Ozturk (2012) | [128] | PB-MNCs1 | RCT | N/A | Fontaine III–IV | 40 (20/20) | Blank | 24.8/mL (CD34+) | IM | 3 | ABI, AR, PFWD, RPS, TcPO2, UH |
Mohammadzadeh (2013) | [127] | PB-MNCs1 | RCT | N/A | Fontaine III–IV | 21 (7/14) | Blank | 900–1200 | IM | 3 | ABI, AR, UH, PFWD |
De Angelis (2015) | [144] | PB-MNCs | NR | ASO | Fontaine IV | 86 (43/43) | Blank5 | 125.65 | IM | 4.5 | AFS, AR, DR, PFWD, RPS, UH |
Tateishi-Yuyama (2002) TACT | [142] | BM-MNCs | NR | ASO | Fontaine III–IV | 252 | Blank | 700–2700 | IM | 6 | ABI, TcPO2, RPS |
BM-MNCs | R | Fontaine III–IV | 223 | Placebo | 889–2800 | IM | 6 | ||||
Arai (2006) | [145] | BM-MNCs | RCT | N/A | Fontaine III–IV | 26 (13/13) | Blank | 1000–3000 | IM | 1 | ABI, TcPO2, RPS |
Dubsky (2013) | [129] | PB-MNCs | NR | N/A | Rutherford 4–6 | 33 (11/22)4 | Blank | 10400 | IM | 6 | AR, TcPO2, UH |
BM-MNCs | 39 (17/22)4 | 1800 | |||||||||
Huang (2007) | [146] | PB-MNCs | NC | ASO | N/A | 76 | N/A | 7200 | IM | 3 | ABI, AR, PFWD, RPS, TcPO2, UH |
BM-MNCs | 74 | 580 | |||||||||
Matoba (2008) | [30] | BM-MNCs | NC | ASO & TAO | Fontaine III–IV | 115 | N/A | N/A | IM | 25.3 | ABI, AFS, DR, PFWD, RPS, TcPO2, UH |
Ruiz-Salmeron (2011) | [120] | BM-MNCs | NC | ASO & others | Rutherford 4–6 | 20 | N/A | 100–400 | IA | 12 | ABI, AR, DR, TcPO2 |
Amann (2009) BONMONT-1 | [114] | BM-MNCs | NC | N/A | Rutherford 4–6 | 12 | N/A | 1100 | IM | 13.5 | ABI, AFS, PFWD, TcPO2 |
BM-TNCs | 39 | 3000 | |||||||||
Walter (2011) PROVASA | [20] | BM-MNCs | RCT | ASO & TAO | Fontaine III–IV | 40 (19/21) | Placebo | 153 | IA | 3 | ABI, AR, DR, RPS, TcPO2, UH |
Li (2013) | [147] | BM-MNCs | RCT | ASO | Fontaine III–IV | 58 (29/29) | Placebo | 10/mL | IM | 6 | ABI, AFS, AR, DR, RPS, UH |
Teraa (2015) JUVENTAS | [148] | BM-MNCs | RCT | ASO | Fontaine IIB–IV | 160 (81/79) | Placebo | 500 | IA | 6 | ABI, AR, DR, TcPO2, UH |
Pignon (2017) BALI | [149] | BM-MNCs | RCT | ASO | Rutherford 4–5 | 36 (17/19) | Placebo | 1300 | IM | 12 | ABI, AR, RPS, TcPO2, UH |
Guo (2018) | [116] | BM-MNCs | NR | TAO | N/A | 59 (40/19) | Blank | 3500 | IM | 129.5 | ABI, AFS, AR, RPS, TcPO2, UH |
Lu (2011) | [150] | BM-MNCs | RCT | ASO | Fontaine IV | 212 | Blank | 930 | IM | 6 | ABI, AR, PFWT, RPS, TcPO2, UH |
BM-MSCs | 202 | 960 | |||||||||
Dash (2009) | [151] | BM-MSCs | RCT | ASO | N/A | 6 (3/3) | Blank | N/A | IM | 3 | PFWD, UH |
Buerger | 18 (9/9) | ||||||||||
Gupta (2013) | [152] | BM-MSCs (allogenic) | RCT | ASO & TAO | Rutherford 4–6 | 20 (10/10) | Placebo | 200 | IM | 6 | ABI, AR, RPS, UH |
Szabò (2013) | [153] | Ves-Cell | RCT | N/A | Fontaine III–IV | 20 (10/10) | Blank | 66.4 | IM | 3 | ABI, AR, DR, PFWD, RPS, TcPO2, UH |
NC | 22.6 | ABI, AFS, AR, DR, PFWD, RPS, TcPO2, UH | |||||||||
Raval (2014) SCRIPT-CLI | [154] | CD133+1 | RCT | ASO | N/A | 10 (3/7) | Placebo | 50–400 | IM | 12 | AFS, AR, DR |
Lara-Hernandez (2010) | [155] | EPCs1 | NC | ASO & TAO | Fontaine III–IV | 28 | N/A | N/A | IM | 14.7 | ABI, RPS, UH |
Kinoshita (2012) | [156] | CD34+1 | NC | ASO & Buerger | Rutherford 4–5 | 17 | N/A | 0.1/kg (LD) 0.5/kg (MD) 1/kg (HD) | IM | 12 | AR, DR, PFWD, RPS, TcPO2, UH |
Dong (2013) | [157] | CD34+1 | NC | ASO, TAO & others | Rutherford 4–5 | 25 | N/A | 0.1/kg (LD) 0.5/kg (MD) 1/kg (HD) | IM | 6 | ABI, AR, DR, PFWT, RPS, TcPO2, UH |
Fujita (2014) | [158] | CD34+1 | NC | ASO & Buerger | Rutherford 4–5 | 11 | N/A | 1/kg | IM | 12 | AR, PFWD, RPS, TcPO2 |
Powell (2012) RESTORE-CLI | [159] | Ixmyelocel-T | RCT | N/A | N/A | 72 (48/24) | Placebo | 35–295 | IM | 12 | AFS, AR, DR |
Losordo (2015) | [160] | CD34+1 | RCT | N/A | Rutherford 4–5 | 28 (16/12) | Placebo | 0.1/kg (LD) 1/kg (HD) | IM | 12 | ABI, AR, DR, PFWD, UH |
Liotta (2018) | [161] | BM-MNCs | R | N/A | Rutherford 4–6 | 17 | Blank5 | 506 | IM | 12 | ABI, PFWD, RPS, TcPO2, UH |
ECEPCs | 23 | 2506 | |||||||||
Fang (2020) | [162] | PB-MNCs1 | RCT | TAO | Rutherford 4–5 | 78 | PB-MNC | 70, 377 | IM | 46,6 | ABI, AFS, PFWT, RPS, TcPO2 |
CD34+1 | 82 | 31, 957 | |||||||||
Sharma (2021) | [163] | BM-MNCs | RCT | ASO & others | Fontaine IIC–IV | 81 (41/40) | Placebo | 71, 51 | IA | 6 | ABI, AR, PFWD, RPS, TcPO2, UH |
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Beltrán-Camacho, L.; Rojas-Torres, M.; Durán-Ruiz, M.C. Current Status of Angiogenic Cell Therapy and Related Strategies Applied in Critical Limb Ischemia. Int. J. Mol. Sci. 2021, 22, 2335. https://doi.org/10.3390/ijms22052335
Beltrán-Camacho L, Rojas-Torres M, Durán-Ruiz MC. Current Status of Angiogenic Cell Therapy and Related Strategies Applied in Critical Limb Ischemia. International Journal of Molecular Sciences. 2021; 22(5):2335. https://doi.org/10.3390/ijms22052335
Chicago/Turabian StyleBeltrán-Camacho, Lucía, Marta Rojas-Torres, and Mᵃ Carmen Durán-Ruiz. 2021. "Current Status of Angiogenic Cell Therapy and Related Strategies Applied in Critical Limb Ischemia" International Journal of Molecular Sciences 22, no. 5: 2335. https://doi.org/10.3390/ijms22052335