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Stem Cells – a Disruptive „Technology“ Changing Medical Practice and Thinking

Stem cell research has become an enormous area of research with an exponentially increasing number of original research publications and clinical trials. However, as usual, it takes at least a decade until the latest insights from bio-science are introduced to medical practice. As is the case with stem cell therapies. While the current hot topic of mesenchymal stem cells (MSCs) has shifted towards the question how stem cells actually interact with the surrounding (paracrine/soluble factors, trophic factors, extracellular vesicles, micro-vesicles, exosomes etc.), clinical research has just started with rather crude MSC injection protocols. In clinical practice, though being used at some specialized sites, MSC therapies have not even found broad acceptance in diseases where their safety/efficacy profile is both proven and superior (or even the only known potential therapy). Researchers and progressive thinking medical professionals being frustrated with the slow adaption and evolution of medicine, hence started calling for translational medicine taking a more important place in society.

Mesenchmal Stem Cells Statistics

The ANOVA Institute for Regenerative Medicine is dedicated to just that: A fully equipped medical institution with an own GMP grade lab – dedicated to translational, regenerative cellular medicine. Respecting guideline procedures but not ignoring latest results from stem cell research or other related research fields.

Next Generation Stem Cell Therapy: Why We Do Not “Just Inject Stem Cells” Anymore

ANOVA has been actively using stem cell therapies since 2010. The gap between what was possible in clinical practice and what was known from research was large. Due to a lack of data, regulations and available products, therapies consisted mostly of image guided injections of bone marrow concentrate (BMC) into different compartments with slightly individualized protocols. The results were often astonishing, but the crudeness of this approach was unsatisfying. With increasing knowledge on the pathways stem cells use to make their effects came a paradigm shift of what is possible in clinical practice today. The evolution is best summarized by Zhang et al. in their 2016 review about extracellular vesicles (EVs):

Stem Cell Secretome Paracrine Factors

“The intense research focus on stem and progenitor cells could be attributed to their differentiation potential to generate new cells to replace diseased or lost cells in many highly intractable degenerative diseases, such as Alzheimer`s disease, multiple sclerosis, and heart diseases.

However, experimental and clinical studies have increasingly attributed the therapeutic efficacy of these cells to their secretion. While stem and progenitor cells secreted many therapeutic molecules, none of these molecules singly or in combination could recapitulate the functional effects of stem cell transplantations.

Recently, it was reported that extracellular vesicles (EVs) could recapitulate the therapeutic effects of stem cell transplantation. Based on the observations reported thus far, the prevailing hypothesis is that stem cell EVs exert their therapeutic effects by transferring biologically active molecules such as proteins, lipids, mRNA, and microRNA from the stem cells to injured or diseased cells. In this respect, stem cell EVs are similar to EVs from other cell types. They are both primarily vehicles for intercellular communication. Therefore, the differentiating factor is likely due to the composition of their cargo. The cargo of EVs from different cell types are known to include a common set of proteins and also proteins that reflect the cell source of the EVs and the physiological or pathological state of the cell source.”

The paracrine activities of stem and progenitor cells are now being extensively explored and mapped. Their major involvement in all essential effects of stem cell therapies (immunomodulation, proliferation, anti-inflammatory, anti-fibrotic, anti-apoptotic, angiogenic, mitogenic, neurotrophic, neuroprotective, chemoattraction) have been shown.

This hence has brought many clinical stem cell groups, us among them, to refocus towards designing new methods with the soluble factors in focus - not the stem cell count. The Stem Cell Secretome Therapy uses MSCs and exposes them to specific stress preconditioning with several proprietary methods to force MSCs to mass produce a secretome with maximum efficacy for the different disease models.

Trophic Factors and Exosome/MV Loads Produced by MSCs and Suggested Functions for Tissue Regeneration/Repair

Angiopoietin: induce angiogenesis, promote cell survival

BDNF: promote neuronal cell survival and differentiation, reduce infarct size

BMPs: regulate tissue homeostasis, promote neurogenesis, induce stromal cell proliferation and migration, promote angiogenesis

CNTF: promote neuronal cell survival

EGF: induce cell proliferation and differentiation

EPO: induce angiogenesis, inhibit apoptosis

FGFs: induce angiogenesis, inhibit apoptosis

Galectins: suppress inflammation, induce stem cell mobilization, inhibit immune cell proliferation

GDNF: promote neuronal cell survival, induce axonal growth, reduce infarct size

G-CSF: induce stem/progenitor cell proliferation, promote neuronal differentiation

HGF: promote progenitor cell mobilization, induce angiogenesis and cell proliferation, inhibit immune cell proliferation

Hemoxygenase-1: promote induction for regulatory T cells

IGFs: induce cell proliferation, inhibit apoptosis

IL-6: stimulate stem/progenitor cell proliferation, induce angiogenesis

IDO: induce regulatory T cells, inhibit T cell activation

IL-1β: suppress inflammation

KGF: induce cell proliferation

MCP-1: induce angiogenesis, induce MSC migration, inhibit apoptosis

MIF: inhibit macrophage migration

NGF: protect neural cells

PDGF: induce cell proliferation

PGE2: suppress inflammation, inhibit immune cell proliferation

SCF: induce stem/progenitor cell proliferation, promote neuronal differentiation

SDF-1: regulate progenitor cell mobilization

TGF-β: induce stem cell differentiation, reduce inflammation/immune activation

TSG-6: suppress immune activation

VEGFs: induce angiogenesis, promote progenitor cell mobilization, inhibit apoptosis

Protein contents of MSC-EVs.

Source of EVs
Protein
Function
Human bone marrow-derived MSCs
CD13, CD29, CD44, CD73, CD105, CD81, CD63, CD90, CD9
Surface antigen
Human bone marrow-derived MSCs
PDGFRB, EGFR, TGFBI, IGF2R
MSCs self-renewal
Human bone marrow-derived MSCs
CTNNBI, RAC1, RAC2, CHP, PRKCB, PPP2RIA, CAMK2D, PRKACA, CAMK2G
MSCs self-renewal and differentiation, Wnt signaling pathway
Human bone marrow-derived MSCs
PPP2RIA, MAPK1, USP9X, COL1A2, CD105, ENG
MSCs differentiation, TGFβ signaling pathway
Human bone marrow-derived MSCs
FLNA, HSPAB, CACNA2D1, CHP, FLNC, PDGFRB, RAP1B, RRAS2, MAP4K4, EGFR, RRAS, GNG12, RAC1, HSPAIA, CDC42, RAC2, NRAS, MAPKl, CD81, FLNB, HSPBl, PRKCB, PRKACA, RAP1A, GNAI2, CAVI, PRDX2, PPP2RIA, SOD1, ITGA1, LPAR1
MSCs differentiation, MAPK signaling pathway
Human bone marrow-derived MSCs
ILK, FABP5, ACSL4
MSCs differentiation, PPAR signaling pathway
Human bone marrow-derived MSCs
ENG, USP9X
MSCs differentiation, BMP signaling pathway
Human adipose tissue-derived MSCs
Neprilysin
Degrade intracellular and extracellular β-amyloid peptide in neuroblastoma cell lines
Human bone marrow-derived MSCs
TIA, TIAR, HuR
T cell internal antigen
Human bone marrow-derived MSCs
Stau1, Stau2
Involved in the transport and stability of mRNA
Human bone marrow-derived MSCs
Ago2
Involved in the miRNA transport and processing
Human umbilical cord-derived MSCs
Wnt4
Enhance the proliferation and migration
Human umbilical cord-derived MSCs
Angiogenin, IL-6, bFGF, UPAR, VEGF, MCP-1, VEGF R2, IGF-I
Promote angiogenesis

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mRNAs expressed in MSC-EVs.

Source of EVs
mRNA
Function
Human bone marrow-derived MSCs
IGF-1R
Enhance cell proliferation
Human bone marrow-derived MSCs
RAX2, OR11H12, OR2M3, DDN, GRIN3A, NIN, BMP15, IBSP, MAGED2, EPX, HK3, COL4A2, CEACAM5, SCNN1G, PKD2L2,
Involved in cell differentiation
Human bone marrow-derived MSCs
CLOCK, IRF6, RAX2, TCFP2, BCL6B
Involved in transcription
Human bone marrow-derived MSCs
HMGN4, TOPORS, ESF1, ELP4, POLR2E, HNRPH2
DNA/RNA binding
Human bone marrow-derived MSCs
SENP2, RBL1, CDC14B, S100A13
Cell cycle
Human bone marrow-derived MSCs
CEACAM5, CLEC2A, CXCR7
Receptors
Human bone marrow-derived MSCs
ADAM15, FUT3, ADM2, LTA4H, BDH2, RAB5A
Involved in metabolism
Human bone marrow-derived MSCs
CRLF1, IL1RN, MT1X
Immune regulation
Human bone marrow-derived MSCs
DDN, MSN, CTNNA1
Cytoskeleton
Human bone marrow-derived MSCs
COL4A2, IBSP
Extracellular matrix
Porcine adipose tissue-derived MSCs
FOXP3, JMJD1C, KDM6B
Encode transcription factors involved in chromosome organization
Porcine adipose tissue-derived MSCs
MDM4, IFT57, PEG3, PDCD4
Encode transcription factors involved in apoptosis
Porcine adipose tissue-derived MSCs
HGF, HES1, TCF4
Encode transcription factors involved in proangiogenic pathways
Porcine adipose tissue-derived MSCs
ZBTB1, ZNF217, ZNF238, ZNF461, ZNF568, ZNF667, ZHX1
Encode zinc-finger transcription factors
Porcine adipose tissue-derived MSCs
TMF1, BAZ2B, JMJD1C, MYNN, NFKBIZ, PEG3, KCNH6, RUNX1T1, SUFU
Encode transcription factors involved in alternative splicing

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miRNAs expressed in MSC-EVs.

Source of EVs
miRNA
Function
Human bone marrow-derived MSCs
miRNA-199b, miRNA-218, miRNA-148a, miRNA-135b, miRNA-221
Regulate osteoblast differentiation
Rats bone marrow-derived MSCs
miRNA-133b
Contribute to neurite outgrowth
Human bone marrow-derived MSCs
miRNA-15a
Inhibit the growth of multiple myeloma cells
Porcine adipose tissue-derived MSCs
miRNA-148a, miR532-5p, miRNA-378, let-7f
Regulate apoptosis, proteolysis angiogenesis, and cellular transport
Human bone marrow-derived MSCs
miRNA-21, miRNA-34a
Regulate cell survival and proliferation
Human bone marrow-derived MSCs
miRNA-23b
Induce dormant phenotypes
Mouse bone marrow-derived MSCs
miRNA-16
Target VEGF; suppress angiogenesis
Human adipose-derived MSCs
miRNA-486-5p, miRNA-10a-5p, let-7a-5p, miRNA-10b-5p, miRNA-191-5p, miRNA-22-3p, miRNA-222-3p, miRNA-21-5p, let-7f -5p, miRNA-127-3p, miRNA-143-3p, miRNA-99b-5p, miRNA-100-5p, miRNA-92a-3p, miRNA-92b-3p, miRNA-146a-5p, miRNA-26a-5p, miRNA-4485, miRNA-146b-5p, miRNA-51a-3p
Promote the migration; involved in replicative senescence, immune modulatory function; regulate cell cycle progression and proliferation; modulate angiogenesis
Human bone marrow-derived MSCs
miRNA-143-3p, miRNA-10b-5p, miRNA-486-5p, let-7a-5p, miRNA-22-3p, miRNA-21-5p, miRNA-222-3p, miRNA-28-3p, miRNA-191-5p, miRNA-100-5p, miRNA-99b-5p, miRNA-92a-3p, miRNA-127-3p, let-7f-5p, miRNA-92b-3p, miRNA-423-5p, let-7i-5p, miRNA-10a-5p, miRNA-27b-3p, miRNA-125b-5p
Promote the migration; involved in ASC replicative senescence, immune modulatory function; regulate cell cycle progression and proliferation; modulate angiogenesis

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The Stem Cell Secretome: The Essence of Mesenchymal Stem Cell Therapies in a Designed Process

As described, we evolved to design a stem cell secretome using mesenchymal stem cells for our injection therapies. The stem cell secretome begins with adipose tissue derived stem cells being expanded using GMP materials and methods only. Once expended to a suitable amount of vital non-senescent MSCs, a proprietary conditioning process is employed to use the MSCs as small factories to produce massive amounts of their secretome. The amount of secretion is estimated 100-10.000x higher than the same amount of stem cells would secrete when injected. After GMP grade quality controls, this conditioned media is now ready for local or systemic injections. Despite the obvious potency advantage, this brings several further advantages:

  • Higher potency by several orders of magnitude
  • Hence excellent repeatability of the treatment as a high amount of injection can be produced from one micro liposuction
  • Extremely high safety because all major risk factors of MSCs are eliminated:
    • local immune responses that can lead long-term rejection of transplanted MSCs
    • disruption of local tissue homeostasis causing inflammation
    • increased risk of tumor formation due to long-term ex vivo expansion and/or local immunosuppression
    • ectopic tissue formation of donor
  • Adaptability of the secretome profile to the requirements
 
Stem Cell Secretome Pictogram
 

References and Literature - Stem Cell Secretome

  1. Konala, Vijay Bhaskar Reddy, et al. "The current landscape of the mesenchymal stromal cell secretome: a new paradigm for cell-free regeneration." Cytotherapy 18.1 (2016): 13-24.
  2. Lopez-Verrilli, M. A., et al. "Mesenchymal stem cell-derived exosomes from different sources selectively promote neuritic outgrowth." Neuroscience 320 (2016): 129-139.
  3. Kim, Hyun Ok, Seong-Mi Choi, and Han-Soo Kim. "Mesenchymal stem cell-derived secretome and microvesicles as a cell-free therapeutics for neurodegenerative disorders." Tissue Engineering and Regenerative Medicine 10.3 (2013): 93-101.
  4. Rani, Sweta, et al. "Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications." Molecular Therapy 23.5 (2015): 812-823.
  5. Zhang, Xiaoyan, et al. "Mesenchymal Stem Cell-Derived Extracellular Vesicles: Roles in Tumor Growth, Progression, and Drug Resistance." Stem Cells International 2017 (2017).
  6. omzikova, Marina O., and Albert A. Rizvanov. "Current Trends in Regenerative Medicine: From Cell to Cell-Free Therapy." BioNanoScience (2016): 1-6.
  7. Zhang, Bin, et al. "Focus on extracellular vesicles: Therapeutic potential of stem cell-derived extracellular Vesicles." International journal of molecular sciences 17.2 (2016): 174.
  8. Katsuda T. et al. (2013). Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Scientific reports, 3, 1197.
  9. Pusic A. D. et al. (2014). IFNγ-stimulated dendritic cell exosomes as a potential therapeutic for remyelination. Journal of neuroimmunology, 266(1), 12-23.
  10. Maumus M, Jorgensen C, Noël D (2013) Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: Role of secretome and exosomes. Biochimie 95:2229–2234. doi: 10.1016/j.biochi.2013.04.017
  11. Drago D, Cossetti C, Iraci N, et al (2013) Biochimie The stem cell secretome and its role in brain repair. Biochimie 95:2271–2285. doi: 10.1016/j.biochi.2013.06.020
  12. Sevivas N, Teixeira FG, Portugal R, et al (2016) Mesenchymal Stem Cell Secretome: A Potential Tool for the Prevention of Muscle Degenerative Changes Associated With Chronic Rotator Cuff Tears. Am J Sports Med. doi: 10.1177/0363546516657827
  13. Hs K (2016) Mesenchymal Stem Cells vs . Mesenchymal Stem Cell Secretome for Rheumatoid Arthritis Treatment. 1:1–2.
  14. Maumus M, Jorgensen C, Noël D (2013) Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: Role of secretome and exosomes. Biochimie 95:2229–2234. doi: 10.1016/j.biochi.2013.04.017
  15. Kapur SK, Katz AJ (2013) Biochimie Review of the adipose derived stem cell secretome. Biochimie 95:2222–2228. doi: 10.1016/j.biochi.2013.06.001
  16. Ranganath SH, Levy O, Inamdar MS, Karp JM (2012) Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 10:244–258. doi: 10.1016/j.stem.2012.02.005
  17. Tran C, Damaser MS (2015) Stem cells as drug delivery methods: Application of stem cell secretome for regeneration. Adv Drug Deliv Rev 82:1–11. doi: 10.1016/j.addr.2014.10.007
  18. Zimmerlin L, Park TS, Zambidis ET, et al (2013) Mesenchymal stem cell secretome and regenerative therapy after cancer. Biochimie 95:2235–2245. doi: 10.1016/j.biochi.2013.05.010
  19. Calamia V, Lourido L, Fernandez-Puente P, et al (2012) Secretome analysis of chondroitin sulfate-treated chondrocytes reveals its anti-angiogenic, anti-inflammatory and anti-catabolic properties. Arthritis Res Ther 14:R202. doi: 10.1186/ar4040
  20. Ranganath SH, Levy O, Inamdar MS, Karp JM (2012) Review Harnessing the Mesenchymal Stem Cell Secretome for the Treatment of Cardiovascular Disease. Stem Cell 10:244–258. doi: 10.1016/j.stem.2012.02.005
  21. Teixeira FG, Carvalho MM, Sousa N, Salgado AJ (2013) Mesenchymal stem cells secretome: A new paradigm for central nervous system regeneration? Cell Mol Life Sci 70:3871–3882. doi: 10.1007/s00018-013-1290-8
  22. Kapur SK, Katz AJ (2013) Review of the adipose derived stem cell secretome. Biochimie 95:2222–2228. doi: 10.1016/j.biochi.2013.06.001
  23. Chang C-P, Chio C-C, Cheong C-U, et al (2013) Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury. Clin Sci (Lond) 124:165–76. doi: 10.1042/CS20120226
  24. Salgado AJ, Sousa JC, Costa BM, et al (2015) Mesenchymal stem cells secretome as a modulator of the neurogenic niche: basic insights and therapeutic opportunities. Front Cell Neurosci 9:1–18. doi: 10.3389/fncel.2015.00249
  25. Ahmed NE-MB, Murakami M, Hirose Y, Nakashima M (2016) Therapeutic Potential of Dental Pulp Stem Cell Secretome for Alzheimer’s Disease Treatment: An In Vitro Study. Stem Cells Int 2016:8102478. doi: 10.1155/2016/8102478
  26. Bhaskar V, Konala R, Mamidi MK, et al (2016) The current landscape of the mesenchymal stromal cell secretome : A new paradigm for cell-free regeneration. Cytotherapy 18:13–24. doi: 10.1016/j.jcyt.2015.10.008
  27. Malda J, Boere J, van de Lest C, et al (2016) Extracellular vesicles - new tool for joint repair and regeneration - IN PRESS. Nat Rev Rheumatol 12:243–249. doi: 10.1038/nrrheum.2015.170
  28. Lener T, Gimona M, Aigner L, et al (2015) Applying extracellular vesicles based therapeutics in clinical trials Á an ISEV position paper. 1:1–31.
  29. Dostert G, Mesure B, Menu P, Velot É (2017) How Do Mesenchymal Stem Cells Influence or Are Influenced by Microenvironment through Extracellular Vesicles Communication ? 5:1–7. doi: 10.3389/fcell.2017.00006
  30. Joshi P, Benussi L, Furlan R, et al (2015) Extracellular vesicles in Alzheimer’s disease: Friends or foes? focus on Aβ-vesicle interaction. Int. J. Mol. Sci. 16:4800–4813.
  31. Gao T, Guo W, Chen M, et al (2016) Extracellular Vesicles and Autophagy in Osteoarthritis.
  32. Katsuda T, Ochiya T (2015) Molecular signatures of mesenchymal stem cell-derived extracellular vesicle-mediated tissue repair. Stem Cell Res Ther 6:212. doi: 10.1186/s13287-015-0214-y
  33. Lener T, Gioma M, Aigner L, et al (2015) Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. J Extracell Vesicles 4:1–31. doi: 10.3402/jev.v4.30087
  34. Xu Y, Guo S, Wei C, et al (2016) The Comparison of Adipose Stem Cell and Placental Stem Cell in Secretion Characteristics and in Facial Antiaging.
  35. Buul GM Van, Villafuertes E, Bos PK, et al (2012) Mesenchymal stem cells secrete factors that inhibit in fl ammatory processes in short-term osteoarthritic synovium and cartilage explant culture. Osteoarthr Cartil 20:1186–1196. doi: 10.1016/j.joca.2012.06.003
  36. Baglio SR, Pegtel DM, Baldini N (2012) Mesenchymal stem cell secreted vesicles provide novel opportunities in ( stem ) cell-free therapy. 3:1–11. doi: 10.3389/fphys.2012.00359
  37. Anderson JD, Pham MT, Contreras Z, et al (2016) Mesenchymal stem cell-based therapy for ischemic stroke. Chinese Neurosurg J 2:36. doi: 10.1186/s41016-016-0053-4
  38. Biology C, Cell R, Eye N, Institutes N (2017) Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through miRNA-Dependent Mechanisms. 1273–1285.

References and Literature - Mesenchymal Stem Cells 'MSCs'

  1. Gu W, Zhang F, Xue Q, Ma Z, Lu P, Yu B. Transplantation of bone marrow mesenchymal stem cells reduces lesion volume and induces axonal regrowth of injured spinal cord. Neuropathology. 2010; 30: 205-217.
  2. Wilkins A, Kemp K, Ginty M, Hares K, Mallam E, Scolding N. Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Res. 2009; 3: 6370
  3. Wei X, Yang X, Han ZP, Qu FF, Shao L, Shi YF. Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin. 2013; 34: 747-754.
  4. Wang S, Qu X, Zhao RC. Clinical applications of mesenchymal stem cells. J Hematol Oncol. 2014; 5: 19.
  5. Farini, Andrea, et al. "Clinical applications of mesenchymal stem cells in chronic diseases." Stem cells international 2014 (2014).
  6. Volarevic, Vladislav, et al. "Concise review: therapeutic potential of mesenchymal stem cells for the treatment of acute liver failure and cirrhosis." Stem Cells 32.11 (2014): 2818-2823.
  7. Ikebe, Chiho, and Ken Suzuki. "Mesenchymal stem cells for regenerative therapy: optimization of cell preparation protocols." BioMed research international 2014 (2014).
  8. Sharma, Ratti Ram, et al. "Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices." Transfusion 54.5 (2014): 1418-1437.
  9. Jo, Chris Hyunchul, et al. "Intra‐articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof‐of‐concept clinical trial." Stem cells 32.5 (2014): 1254-1266.
  10. Squillaro, Tiziana, Gianfranco Peluso, and Umberto Galderisi. "Clinical trials with mesenchymal stem cells: an update." Cell transplantation 25.5 (2016): 829-848.
  11. Orozco, Lluis, et al. "Treatment of knee osteoarthritis with autologous mesenchymal stem cells: two-year follow-up results." Transplantation 97.11 (2014): e66-e68.
  12. Filardo, Giuseppe, et al. "Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics." Knee surgery, sports traumatology, arthroscopy 21.8 (2013): 1717-1729.
  13. Jo, Chris Hyunchul, et al. "Intra‐articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof‐of‐concept clinical trial." Stem cells 32.5 (2014): 1254-1266.
  14. Vangsness, C. Thomas, et al. "Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy." J Bone Joint Surg Am 96.2 (2014): 90-98.

References and Literature - Bone Marrow Concentrate 'BMC'

  1. He Y, He W, Qin G, Luo J, Xiao M. Transplantation KCNMA1 modified bone marrow-mesenchymal stem cell therapy for diabetes mellitus-induced erectile dysfunction. Andrologia. 2014;46(5):479-486. doi:10.1111/and.12104.
  2. Mathiasen AB, Qayyum AA, Jørgensen E, et al. Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial ({MSC}-{HF} trial). Eur Heart J. 2015;36(27):1744-1753. doi:10.1093/eurheartj/ehv136.
  3. Mathiasen AB, Qayyum AA, Jørgensen E, et al. Interventional cardiology Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure?: a randomized placebo-controlled trial. 2015. doi:10.1093/eurheartj/ehv136.
  4. Liao H-T, Chen C-T. Osteogenic potential: Comparison between bone marrow and adipose-derived mesenchymal stem cells. World J Stem Cells. 2014;6(3):288-295. doi:10.4252/wjsc.v6.i3.288.
  5. Terai S, Ishikawa T, Omori K, et al. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells. 2006;24(10):2292-2298. doi:10.1634/stemcells.2005-0542.
  6. 2015_Cao_Spine-Journal_Bone-marrow-mesenchymal-stem-cells-slow-intervertebral-disc-degeneration-through-the-NF-?B-pathway.pdf.
  7. Zhao J, Zhang Q, Wang Y, Li Y. Uterine Infusion With Bone Marrow Mesenchymal Stem Cells Improves Endometrium Thickness in a Rat Model of Thin Endometrium. Reprod Sci. 2015;22(2):181-188. doi:10.1177/1933719114537715.
  8. Fekete N, Rojewski MT, Fürst D, et al. GMP-compliant isolation and large-scale expansion of bone marrow-derived MSC. PLoS One. 2012;7(8). doi:10.1371/journal.pone.0043255.
  9. Elman JS, Li M, Wang F, Gimble JM, Parekkadan B. A comparison of adipose and bone marrow-derived mesenchymal stromal cell secreted factors in the treatment of systemic inflammation. 2014:4-11.
  10. Li C, Wu X, Tong J, et al. Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno-free conditions for cell therapy. Stem Cell Res Ther. 2015;6(1):55. doi:10.1186/s13287-015-0066-5.
  11. Books J, Sign R. Safety of Intracavernous Bone Marrow-Mononuclear Cells for Postrad ... Safety of Intracavernous Bone Marrow-Mononuclear Cells for Postradical Prostatectomy Erectile Dysfunction?: An Open Dose-Escalation Pilot Study Safety of Intracavernous Bone Marrow-Mon. 2017:2015-2017.
  12. Rinker TE, Hammoudi TM, Kemp ML, Lu H, Temenoff JS. Interactions between mesenchymal stem cells, adipocytes, and osteoblasts in a 3D tri-culture model of hyperglycemic conditions in the bone marrow microenvironment. Integr Biol (Camb). 2014;6(3):324-337. doi:10.1039/c3ib40194d.
  13. Al-sayegh H, Bashir J, Goodyear S, Freeman MD. A prospective multi-site registry study of a specific protocol of autologous bone marrow concentrate for the treatment of shoulder rotator cuff tears and osteoarthritis. 2015:269-276.
  14. Rager TM, Olson JK, Zhou Y, Wang Y, Besner GE. Exosomes secreted from bone marrow-derived mesenchymal stem cells protect the intestines from experimental necrotizing enterocolitis. J Pediatr Surg. 2016;51(6):942-947. doi:10.1016/j.jpedsurg.2016.02.061.
  15. Tate-oliver K, Alexander RW. Density Platelet-Rich Plasma or Bone Marrow.
  16. Tang K, Yan J, Shen Y, et al. Tracing type 1 diabetic Tibet miniature pig ? s bone marrow mesenchymal stem cells in vitro by magnetic resonance imaging. 2014;6:123-131. doi:10.1111/1753-0407.12084.
  17. Wang X, Mamillapalli R, Mutlu L, Du H, Taylor HS. Chemoattraction of bone marrow-derived stem cells towards human endometrial stromal cells is mediated by estradiol regulated CXCL12 and CXCR4 expression. Stem Cell Res. 2015;15(1):14-22. doi:10.1016/j.scr.2015.04.004.
  18. Rambaldi A, Capelli C, Domenghini M, et al. Human platelet lysate allows expansion and clinical grade production of mesenchymal stromal cells from small samples of bone marrow aspirates or marrow filter washouts. 2007:785-791. doi:10.1038/sj.bmt.1705798.
  19. Mushtaq M, Williams AR, Suncion VY, et al. Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy The TAC-HFT Randomized Trial. 2015;16960. doi:10.1001/jama.2013.282909.
  20. 2014 Autografting of bone marrow mesenchymal stem cells alleviates streptozotocin induced diabetes in miniature pigs.pdf.
  21. Program T, Marga- P, Kingdom U. Bone Marrow Therapies for Chronic Heart Dis- ease. 2015:1-12. doi:10.1002/stem.2080.
  22. Biology C, Cell R, Eye N, Institutes N, Infor- AS. Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through miRNA-Dependent Mechanisms. 2017:1273-1285. doi:10.1002/sctm.12056.
  23. Jeong Y, Kyu H, Hwa H, Chan Y. Cellular Physiology and Biochemistr y Biochemistry Direct Comparison of Human Mesenchymal Stem Cells Derived from Adipose Tissues and Bone Marrow in Mediating Neovascularization in Response to Vascular Ischemia. Cell Physiol Biochem. 2007;20:867-876.
  24. Shutian S, Shaoping N, Xingxin W, et al. GW25-e3198 The combination of transforming growth factor ?1 and 5-azacytidine improve the differentiation effects of rat Bone marrow mesenchymal stem cells into cardiomyocytes. J Am Coll Cardiol. 2014;64(16):C21. doi:10.1016/j.jacc.2014.06.105.
  25. Narita T, Suzuki K. Bone marrow-derived mesenchymal stem cells for the treatment of heart failure. Heart Fail Rev. 2014:53-68. doi:10.1007/s10741-014-9435-x.
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