MSC Based Therapies to Prevent or Treat BPD—A Narrative Review on Advances and Ongoing Challenges
Abstract
:1. Introduction
2. What Are the Proven Benefits of MSC Application within the Injury-Repair-Regeneration Cascade?
3. Is the Therapeutic Efficacy of MSC to Prevent or Treat BPD in the Preclinical Setting Well-Founded?
Experimental Lung Disease Model | Species | Cell Source | MSC Species | Dose (Cells) | Application Route | Time Point of Application | Effect on Survival | Histologic Evaluation | Functional Properties | Molecular Changes | Reference |
---|---|---|---|---|---|---|---|---|---|---|---|
hyperoxia 90%, P1–P5 | mice | human | BMMSC | 2.5 × 105 | i.t. | P5 | attenuation of M1 macrophages, collagen deposition, retention of M2 macrophages | [44] | |||
hyperoxia 80%, P1–P14 | mice | human | UCBMSC | 2 × 105 | i.t. | P5 | no effect (100% survival in all groups) | attenuation of alveolar and vascular lung pathology | reduction of formyl peptide receptor-1 expression and similar effects on apoptosis, VEGFA levels and influx of macrophages and neutrophils as in FPR-1 knockout mice | [43] | |
hyperoxia 90%, P1–P7 | mice | human | UCTMSC | 1 × 105 or 5 × 105 or 1 × 106 | i.n. or i.p. | P5 | reduced alveolar remodeling | normalization of lung function parameters | [32] | ||
hyperoxia 75%, P1–P14 | mice | mice | BMMSC | 5 × 104 | i.v. | P4 | preserved alveolar and vascular structures | reduced influx of macrophages/neutrophils | [29] | ||
hyperoxia 60%, P1–P45 | mice | mice | BMMSC | 1 × 105 | i.p. | P7 | increased survival | better preserved alveolar structures, attenuated fibrosis | inhibition of IL-1β, TNF-α, TGF-β1 upregulation | [31] | |
hyperoxia 60%, P1–P14 | mice | mice | BMMSC | 1 × 106 | i.v. | P1 | reduced alveolar hypoplasia | better preserved VEGFA, reduced TGFβ1 | [34] | ||
hyperoxia 60%, P1–P14 | mice | mice | BMMSC | 1 × 106 | i.v. | P1 and P7 | improved airway structures | improved PECAM and VEGFA, reduced MMP-9 | [36] | ||
hyperoxia 60%, P1–P14 | rat | human | AFMSC | 1.5 × 106 | i.t. | P21 | 100% survival in all groups | better preserved alveolar and vascular structures | reduced IL1β, IL6, IF-g, TGF-β1, apoptosis induction, preserved VEGFA | [52] | |
hyperoxia 95%, P1–P14 | rat | human | BMMSC | 3 × 105 (P4) or 6 × 105 (P14) | i.t. | P4 or P14 | attenuated alveolar and vascular changes by P4/P14 | improved exercise capacity | [61] | ||
hyperoxia 85%, P1–P14 | rat | human | PTMSC | 1 × 105 | i.t. | P5 | no effect | reduced alveolar hypoplasia | reduced apoptosis, IL1β, MIP-2 | [39] | |
hyperoxia 85%, P1–P14 | rat | human | PTMSC | 1 × 105 | i.t. | P5 | no effect | attenuation of alveolar rarefication | reduced IL6, TNF-α, activation of the renin-angiotensin system | [40] | |
hyperoxia 85%, P4–P15 | rat | human | PTMSC | 9 × 105 | i.v. | P15 | no effect | improved alveolarization, vascularization | associated with suppression of sonic hedgehog signaling | [47] | |
hyperoxia 80%, P1–P14 | rat | human | PTMSC | 1 × 106 | i.t. | P7 | increased survival | amelioration of lung injury | [64] | ||
hyperoxia 90%, P1–P14; 60%, P15–P21 | rat | human | UCBMSC | 5 × 105 | i.t. | P3 and/or P10 | increased survival for treatment P3/P3 + P10 | better preserved alveolar structures for P3/P3 + P10 | reduced oxidative stress, TNF-α, IL-1β, IL6, TGF-β, TIMP1, CXCL7, RANTES, L-selectin, sICAM-1, better preserved HGF, VEGFA for P3/P3 + P10 | [54] | |
hyperoxia 95%, P1–P14 | rat | human | UCBMSC | 5 × 103 or 5 × 104 or 5 × 105 | i.t. | P5 | increased survival in medium and high MSC dosage intervention groups | dose-response relationship of attenuation of lung injury | dose response relationship for attenuation of myeloperoxidase activity, TNF-α, IL1β, IL6, TGF-β and oxidative stress | [51] | |
hyperoxia 90%, P1–P14 | rat | human | UCBMSC | 1 × 105 | i.t. | P5 | increased survival | reduction of lung injury | increased M2 macrophages IL10, reduced M1 macrophages, IL6, IL8 | [49] | |
hyperoxia 90%, P1–P14 | rat | human | UCBMSC | 1 × 105 | i.t. | P5 | increased survival | MSC with high decorin expression better preserved alveolar structures | MSC with high decorin expression inhibited IL6, IL8, retained IL10 decorin responsible for M2 macrophage polarization | [46] | |
hyperoxia 90%, P1–P14 | rat | human | UCBMSC; ATMSC | 5 × 105 | i.t. | P5 | no effect | reduced alveolar hypoplasia | [33] | ||
hyperoxia 90%, P1–P14 | rat | human | UCBMSC | 5 × 105 (i.t.) or 2 × 106 (i.v.) | i.t. or i.v. | P5 | increased survival | reduced alveolar hypoplasia | reduced macrophages, i.t. additional inhibition of apoptosis, MIP1α, TNF-α, IL6, CTGF, better preserved VEGFA, HGF | [35] | |
hyperoxia 90%, P1–P14 | rat | human | UCBMSC | 5 × 105 | i.t. | P5 | hyperoxia lower than normoxia, hyperoxia + MSC similar to normoxia | improved airway and brain structures | reduced IL-1α, IL-1β, IL6, TNF-α, better preserved VEGFA | [37] | |
hyperoxia 90%, P1–P14 | rat | human | UCBMSC | 5 × 105 | i.t. | P5 | benefits for alveolarization, angiogenesis | beneficial effect on cell death, activated macrophages, IL1α, IL1β, IL6, TNF-α | [42] | ||
hyperoxia 90%, P1–P14 | rat | human | UCBMSC | 5 × 105 | i.t. | P5 | no effect | improved alveolar and vascular structures | reduced neutrophils/macrophages, inflammatory foci | [55] | |
hyperoxia 90%, P1–P14 | rat | human | UCBMSC | 5 × 105 | i.t. | P5 | benefits on alveologenesis and vasculogenesis | reduced apoptosis, macrophages, IL1α, IL1β, IL6, TNFα | [56] | ||
hyperoxia 95%, P1–P14 | rat | human | UCBMSC | 2 × 106 i.t. or 5 × 105 i.p. | i.t. or i.p. | P5 | not significantly improved | i.t. only: preservation of alveolar structures | reduced apoptotis, myeloperoxidase activity and IL6 level; i.t. only: attenuated TNF-α, TGF-β1, α-SMA expression, collagen deposition | [28] | |
hyperoxia 80%, P1–P21 | rat | human | UCTMSC | 3 × 105 | i.t. | P7 | increased survival | attenuation of lung alterations | reduced elastase activity, aberrant elastin deposition, TGF-β1 | [41] | |
hyperoxia 60%, P4–P7 | rat | human | UCTMSC | 5 × 105 | i.n. | P4, P10 and P20 | no effect | improved alveolarization and vascularization | associated with gene regulation for angiogenesis, immunomodulation, wound healing, cell survival | [48] | |
hyperoxia 60%, P1–P14 | rat | human | UCTMSC | in total 6 × 106 | i.t. | P3, P7 and P10 | no effect (100% survival in all groups) | retention of alveolarization, vascularization | [45] | ||
hyperoxia 95%, P3–P10 | rat | rat | BMMSC | 5 × 104 | i.v. | preserved alveolar structures | attenuation of TGFβ, TNF-α upregulation | [27] | |||
hyperoxia 95%, P1–P14 | rat | rat | BMMSC | 1 × 105 | i.t. | P4 or P14 | increased survival | preserved alveolar and vascular structures | reduced pulmonary hypertension, improved exercise tolerance | [30] | |
hyperoxia 80%, P1–P15 | rat | rat | BMMSC | 1 × 105 | i.v. | P5 | no effect | improved alveolar and vascular structures | reduced pulmonary hypertension | reduced M1 macrophages, IL6 | [76] |
hyperoxia 95%, P3–P10 | rat | rat | BMMSC | 1 × 105 | i.v. | P10 | attenuated lung injury | suppression of TNF-α, TGF-β upregulation | [50] | ||
hyperoxia 95%, P3–P10 | rat | rat | BMMSC | 1 × 105 | i.v. | P10 | increased survival | preservation of VEGFA, AQP5, SPC expression | [67] | ||
hyperoxia 90%, P2–P16 | rat | rat | BMMSC | 2 × 106 | i.t. | P9 | acute and long-term improvements in alveolar and vascular development | reduced IL1β and IL6 upregulation, preserved Ang-1 and VEGFA | [53] | ||
hyperoxia 85–90%, P2–P21 | rat | rat | BMMSC | 1 × 106 | i.t. | P7 | improved airway and vasculature structures | [66] | |||
hyperoxia 85%, P1–P21 | rat | rat | BMMSC | 1 × 106 | i.t. | P7 | improved alveolarization and angiogenesis | reduced influx of inflammatory macrophages, neutrophils, reduced IL-1β, improved IL-10 | [38] |
Experimental Lung Disease Model | Species | Cell Source | MSC Species | Dose (Cells) | Application Route | Time Point of Application | Effect on Survival | Histologic Evaluation | Functional Properties | Molecular Changes | Reference |
---|---|---|---|---|---|---|---|---|---|---|---|
intrauterine LPS | mice | mice | BMMSC | 2 × 106 | i.a. | G17 | better preserved lung maturation | ErbB4 required for MSC action | [59] | ||
intrauterine LPS plus hyperoxia 85%, P1–P14 | rat | human | PTMSC | 3 × 105 or 1 × 106 | i.t. | P5 | increased survival from P6 to P9, no difference at P14 | reduced alveolar and vascular hypoplasia, | inhibition of TNF-α, IL6, CTGF, collagen density, better preserved VEGFA | [57] | |
intrauterine LPS | rat | human | PTMSC | 3 × 105 or 1 × 106 | i.t. | P5 | reduced alveolar and vascular hypoplasia | reduced influx of inflammatory macrophages | [58] |
Experimental Lung Disease Model | Species | Cell Source | MSC Species | Dose (Cells) | Application Route | Time Point of Application | Effect on Survival | Histologic Evaluation | Functional Properties | Molecular Changes | Reference |
---|---|---|---|---|---|---|---|---|---|---|---|
hyperoxia 90%, P1–P14 | rat | human | UCBMSC; ATMSC | 5 × 105 | i.t. | P5 | no effect on survival | better preserved alveolar structures by UCBMSC than ATMSC; improved angiogenesis only after UCBMSC | decreased cell death, macrophage influx, inflammatory cytokine levels only after UCBMSC | [33] |
4. Do the Results from MSC Application within First Phase I Clinical Trials Justify to Further Pursue This Approach?
5. Is MSC Application Safe?
6. Is the Secretome the Key to Practicality and Safety of MSC Application?
7. Is Cell Engineering the Ultimate Step to Therapy Success?
8. Concluding Remarks
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Drug | Intervention | Control | Odds Ratio | Number Needed to Treat | Reference |
---|---|---|---|---|---|
surfactant 1 | 437/805 | 517/791 | 0.83 | 9 | [17] |
(54.3%) | (65.4%) | (0.77–0.90) | |||
vitamin A | 486/1000 | 546/1000 | 0.87 | 11 | [16] |
(48.6%) | (54.6%) | (0.77–0.99) | |||
caffeine | 350/963 | 447/954 | 0.64 | 9.5 | [12,13,14] |
(36.3%) | (46.9%) | (0.52–0.78) | |||
azithromycin | 81/161 | 90/149 | 0.83 | 10 | [15] |
(50.3%) | (60.4%) | (0.71–0.97) | |||
corticosteroids | 498/1964 | 633/1965 | 0.79 | n.a. | [18] |
<8 days | (25.4%) | (32.3%) | (0.72–0.87) | ||
corticosteroids | 143/295 | 183/285 | 0.77 | n.a. | [19] |
>7 days | (48.5%) | (64.2%) | (0.67–0.88) |
Experimental Lung Disease Model | Species | Cell Source | MSC Species | MSC Preparation | Dose (Cells) | Application Route | Time Point of Application | Histologic Evaluation | Functional Properties | Molecular Changes | Reference |
---|---|---|---|---|---|---|---|---|---|---|---|
hyperoxia 75%, P1–P7 | mice | human | BMMSC; UCTMSC | exosomes | 50 µL concentrate, equivalent to product of 5 × 105 MSCs over 36 h | i.v. | P4 | amelioration of alveolar simplification, fibrosis, pulmonary vascular remodeling by UCTMSC and BMMSC derived exosomes equally effective | amelioration of lung function and pulmonary hypertension | suppression of M1 macrophages, IL6, TNF-α, CCL2, CCL5, CCL7, augmentation of M2-like macrophages, CCL17 | [97] |
hyperoxia >95%, P1–P4 | mice | human | UCTMSC | conditioned medium or exosomes | 100 µL concentrate, equivalent to 7.6 × 105 MSCs | i.p. | P2 and P4 | improvements in lung and cardiac pathology | improved cardiovascular function | reduced influx of inflammatory cells, neutrophils | [99] |
hyperoxia 75%, P1–P14 | mice | human | UCTMSC | exosomes | 100 µL concentrate, equivalent to 1 × 106 MSCs | i.v. | P4 or 4 times on P18, P25, P32 and P39 | in all application settings improvements in alveolar and vascular development, less fibrosis | improved exercise capacity, ameliorated pulmonary hypertension | [100] | |
hyperoxia 75%, P1–P14 | mice | mice | BMMSC | conditioned medium | 50 µL concentrate, equivalent to 5 × 104 MSCs | i.v. | P4 | preserved alveolar and vascular structures | reduced macrophages, neutrophils | [29] | |
hyperoxia 75%, P1–P14 | mice | mice | BMMSC | conditioned medium | 50 µL concentrate, equivalent to 5 × 104 MSCs | i.v. | P4 | preserved lung structure | increase in bronchioloalveolar stem cells | [68] | |
hyperoxia 75%, P1–P14 | mice | mice | BMMSC | conditioned medium | 50 µL (10µg MSC-CM protein), equivalent to 5 × 105 MSCs | i.v. | P14 | partially reversed alveolar and vascular injury, reversal of right ventricular hypertrophy | improved lung function, reversal of pulmonary hypertension, peripheral pulmonary vascular remodeling | [60] | |
hyperoxia 80%, P1–P14 | rat | human | AMMSC | conditioned medium or exosomes | 50 µL conditioned media or 300 ng exosomes in 50 µL, cell equivalent not available | i.t. | P7 | amelioration of lung injury not as efficient as for AMMSC | [64] | ||
hyperoxia 90%, P1–P14 | rat | human | UCBMSC | exosomes | 20 µg protein, derived from 5 × 105 MSCs | i.t. | P5 | [42] | |||
hyperoxia 85%, P1–P14 | rat | human | UCTMSC | exosomes | 20 µg protein | i.t. | P7 | restoration of alveolar structure | improved lung function | improved number of ki67, SPC and CD31 positive cells and VEGFA expression, reduced TUNEL positive cells, PTEN and cleaved caspase-3 expression | [101] |
hyperoxia 60%, P1–P14 | rat | human | UCTMSC | exosomes | 50 µL concentrate, equivalent to 8 × 108, 4.5 × 108 and 3 × 108 exosomes at P3, P7 and P10, cell equivalent not available | i.t. | P3, P7 and P10 | better preserved alveolarization, vasculature development compared to MSC | [45] | ||
hyperoxia 95%, P1–P15 | rat | rat | BMMSC | conditioned medium | 1 µL/g body weight concentrate, equivalent to 1.5 × 106 MSCs | i.p. | daily P1–P21 | better preserved alveolar growth, prevention of pulmonary hypertension | [96] | ||
hyperoxia 90%, P2–P16 | rat | rat | BMMSC | conditioned medium | 50 µL concentrate, equivalent to 2 × 106 MSCs | i.t. | P9 | improvements in alveolar and vascular development, conditioned medium as effective as MSC | reduced IL1β,IL6, preserved Ang-1, VEGFA | [53] | |
hyperoxia 85%, P1–P14 | rat | rat | BMMSC | exosomes | 50 µL concentrate (3.4 × 109 exosomes, product of approx. 106 cells) | i.p. | daily P2-P15 | protection of alveolarization, angiogenesis and reduction of right heart hypertrophy | [98] | ||
hyperoxia 95%, P1–P14 | rat | rat | UCBMSC | conditioned medium | 7 µL/g body weight; harvested at 90% cell confluency, cell equivalent not available | i.t. | daily P4-P21 or daily P14-P28 | similarly attenuated alveolar and vascular changes as by early and late MSC | similarly improved exercise capacity | [61] |
Experimental Lung Disease Model | Species | Cell Source | MSC Species | Modification | Dose (Cells) | Application Route | Time Point of Application | Histologic Evaluation | Functional Properties | Molecular Changes | Reference |
---|---|---|---|---|---|---|---|---|---|---|---|
hyperoxia 60%, P1–P14 | mice | mice | BMMSC | MSC plus recombinant erythropoetin | 1 × 106 MSCs and 5000 U/kg EPO | i.v. | P1 and P7 | improved airway structures | improved PECAM, VEGFA, reduced MMP-9 | [36] | |
hyperoxia 85%, P1–P14 | rat | human | PTMSC | MSC plus natural surfactant | 1 × 105 MSCs and 10 µL surfactant (corr. to 35 mg/kg phospholipids) | i.t. | P5 | no additional benefit for alveolar hypoplasia | [39] |
Experimental Lung Disease Model | Species | Cell Source | MSC Species | MSC Preparation | Modification | Dose (Cells) | Application Route | Time Point of Application | Histologic Evaluation | Functional Properties | Molecular Changes | Reference |
---|---|---|---|---|---|---|---|---|---|---|---|---|
hyperoxia 95%, P1–P15 | rat | rat | BMMSC | conditioned medium | hyperoxic preconditioning of MSC | 1 µL/g body weight equivalent to 1.5 × 106 MSCs | i.p. | daily P1–P21 | better preserved alveolar growth, prevention of pulmonary hypertension | [96] |
Experimental Lung Disease Model | Species | Cell Source | MSC Species | MSC Preparation | Modification | Dose (Cells) | Application Route | Time Point of Application | Histologic Evaluation | Functional Properties | Molecular Changes | Reference |
---|---|---|---|---|---|---|---|---|---|---|---|---|
hyperoxia >95%, P1–P4 | mice | human | UCTMSC | exosomes | MSC with knockdown of TSG-6 | 100 µL concentrate, equivalent to 7.6 × 105 MSCs | i.p. | P2 and P4 | abrogation of improvements in lung and cardiac pathology | influx of inflammatory cells and neutrophils no longer inhibited | [99] | |
hyperoxia 90%, P1–P14 | rat | human | UCBMSC | MSC with knockdown of decorin | 1 × 105 | i.t. | P5 | attenuated beneficial effects on alveolar structures | reverted IL6, IL8 upregulation, reduced IL10, M1 macrophage polarization retained | [46] | ||
hyperoxia 90%, P1–P14 | rat | human | UCBMSC | MSC with knockdown of PTX3 | 1 × 105 | i.t. | P5 | attenuation of reduced lung injury | attenuation of macrophage shift from M1 to M2, IL10, preserved IL6, IL8 | [49] | ||
hyperoxia 90%, P1–P14 | rat | human | UCBMSC | MSC with knockdown of VEGFA | 5 × 105 | i.t. | P5 | beneficial effects on alveologenesis, vasculogenesis abolished | reduced apoptosis, macrophages, IL1α, IL1β, IL6, TNFα abolished | [56] | ||
hyperoxia 90%, P1–P14 | rat | human | UCBMSC | exosomes | MSCs with knockdown of VEGFA | 20 µg EVs, derived from 5 × 105 MSCs | i.t. | P5 | attenuation of beneficial effects on alveolarization, angiogenesis | attenuation of beneficial effects on cell death, activated macrophages, s IL1α, IL1β, IL6, TNF-α | [42] | |
hyperoxia 80%, P1–P15 | rat | rat | BMMSC | MSC transfected with 7ND-CCL2 | 1 × 105 | i.v. | P5 | improved alveolar and vascular structures | reduced pulmonary hypertension | reduced M1 macrophages, IL6 | [76] | |
hyperoxia 85%, P1–P21 | rat | rat | BMMSC | MSC with knockdown of SDF-1 | 1 × 106 | i.t. | P7 | attenuation of all beneficial MSC effects | reduced inflammatory macrophages, IL1β and improved IL10 prohibited | [38] |
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Goetz, M.J.; Kremer, S.; Behnke, J.; Staude, B.; Shahzad, T.; Holzfurtner, L.; Chao, C.-M.; Morty, R.E.; Bellusci, S.; Ehrhardt, H. MSC Based Therapies to Prevent or Treat BPD—A Narrative Review on Advances and Ongoing Challenges. Int. J. Mol. Sci. 2021, 22, 1138. https://doi.org/10.3390/ijms22031138
Goetz MJ, Kremer S, Behnke J, Staude B, Shahzad T, Holzfurtner L, Chao C-M, Morty RE, Bellusci S, Ehrhardt H. MSC Based Therapies to Prevent or Treat BPD—A Narrative Review on Advances and Ongoing Challenges. International Journal of Molecular Sciences. 2021; 22(3):1138. https://doi.org/10.3390/ijms22031138
Chicago/Turabian StyleGoetz, Maurizio J., Sarah Kremer, Judith Behnke, Birte Staude, Tayyab Shahzad, Lena Holzfurtner, Cho-Ming Chao, Rory E. Morty, Saverio Bellusci, and Harald Ehrhardt. 2021. "MSC Based Therapies to Prevent or Treat BPD—A Narrative Review on Advances and Ongoing Challenges" International Journal of Molecular Sciences 22, no. 3: 1138. https://doi.org/10.3390/ijms22031138
APA StyleGoetz, M. J., Kremer, S., Behnke, J., Staude, B., Shahzad, T., Holzfurtner, L., Chao, C. -M., Morty, R. E., Bellusci, S., & Ehrhardt, H. (2021). MSC Based Therapies to Prevent or Treat BPD—A Narrative Review on Advances and Ongoing Challenges. International Journal of Molecular Sciences, 22(3), 1138. https://doi.org/10.3390/ijms22031138