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

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

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

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

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  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.
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  8. Katsuda T. et al. (2013). Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Scientific reports, 3, 1197.
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  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
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  31. Gao T, Guo W, Chen M, et al (2016) Extracellular Vesicles and Autophagy in Osteoarthritis.
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  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
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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.
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  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.
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  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'

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