Fundamental to bioregulatory medicine: The role of the microenvironment as critical supporter of healthy cells.

1. Cellular
Microenvironment
Information
Regulation.

2. Objective
• To understand
the Cellular
Microenvironment
Information
Regulation.

3. Introduction.
• Fundamental to
bioregulatory medicine:
–The role of the
microenvironment as…
•Critical supporter
of healthy cells.

4. Bibliographic reference.
• Buttle DJ.
• Factors controlling
matrix turnover in
health and disease.
• Biochem Soc Trans. Aug
2007;35(Pt 4):643-646.

5. Introduction.
• Fundamental to
bioregulatory medicine:
–The role of the
microenvironment as
•Conduit of biological
information in tissues.

6. Bibliographic reference.
• Xu R, Boudreau A, Bissell MJ.
• Tissue architecture and function:
dynamic reciprocity via
extra- and intra-cellular matrices.
• Cancer Metastasis Rev.
Jun 2009;28(1-2):167-176.

7. Introduction.
• A healthy
microenvironment
encompasses the
biochemical and
biophysical signals…
–That a cell receives.

8. Introduction.
• Signals from:
–The extracellular
matrix (ECM),
–Neighboring cells,
–The immune system.

9. Introduction.
• Signals are necessary
for a cell and tissue
to maintain…
–Its function and
autoregulatory ability.
• Cell turnover.

10. Bibliographic reference.
• Pellettieri J,
Sanchez Alvarado A.
• Cell turnover and adult
tissue homeostasis: from
humans to planarians.
• Annu Rev Genet.
2007;41:83-105.

11. Introduction.
• Bioregulatory medicine
considers the cell and
its ECM…
–As the collective
functional unit
in higher organisms.
•Not the cell alone.

12. Extracellular matrix.
• Is itself an
informational
entity…
–An extension of
the intracellular
molecular network.

13. Extracellular matrix.
• Integrates structural
and functional
signals…
–Allow for
differentiation
in cell shape
and structure.

14. Extracellular matrix.
• Communication
between the ECM
and the cell nucleus,
–is dynamic and
reciprocal.

15. Bibliographic reference.
• Bissell MJ, Rizki A, Mian IS.
• Tissue architecture:
the ultimate regulator of
breast epithelial function.
• Curr Opin Cell Biol.
Dec 2003;15(6):753-762.

16. Extracellular matrix.
• Dynamic
reciprocity…
–Explains
information
flows in the
microenvironment.

17. Extracellular matrix.
• The mature local
microenvironment,
–Tightly regulates and
controls cellular fates…
•To maintain molecular
order and healthy cell
turnover

18. Extracellular matrix.
• The ECM, intracellular
cytoskeleton and
nuclear matrix,
–Are directly
interconnected through a
chain of commonly
utilized molecules.

19. Bibliographic reference.
• Huang S, Ingber DE.
• A non-genetic basis for cancer
progression and metastasis:
self-organizing attractors
in cell regulatory networks.
• Breast Dis. 2006;26:27-54.

20. Extracellular matrix.
• The dynamic,
bidirectional cross talk
between the ECM and
the cell membrane…
–Influences gene
expression.

21. Extracellular matrix.
• Connecting:
–ECM-ECM receptor
interactions to
the cytoskeleton,
nuclear matrix,
chromatin.
•back again

23. Bibliographic reference.
• Nelson CM, Bissell MJ.
• Of extracellular matrix, scaffolds,
and signaling: tissue architecture
regulates development,
homeostasis, and cancer.
• Annu Rev Cell Dev Biol.
2006;22:287-309.

24. Extracellular matrix.
• Cellular
Microenvironment
Information Regulation
–Considers the tissue
microenvironment
•The terrain
of the body.

25. Bibliographic reference.
• Genuis SJ.
• What's out there
making us sick?
• J Environ Public Health.
2012;2012:605137.

26. The terrain of the body.
• Where signals of
various origins:
–Biochemical,
–Physical,
–Neural,
•Are coupled and processed.

27. The terrain of the body.
• Can in turn influence
network robustness.

28. The terrain of the body.
• Excessive breakdown of the ECM
components associated with altered
levels of reactive oxygen species
–Result in the modification of
multiple molecular networks
•across tissues and subsequent
pathology .

29. Bibliographic reference.
• Kar S, Subbaram S,
Carrico PM, Melendez JA.
• Redox-control of matrix
metalloproteinase-1: a critical link
between free radicals, matrix
remodeling and degenerative disease.
• Respir Physiol Neurobiol.
Dec 31 2010;174(3):299-306.

30. Bibliographic reference.
• Kashihara N, Haruna Y,
Kondeti VK, Kanwar YS.
• Oxidative stress in diabetic
nephropathy.
• Curr Med Chem. 2010;17(34):4256-
4269.

31. Bibliographic reference.
• Vacek TP, Vacek JC, Tyagi SC.
• Mitochondrial mitophagic
mechanisms of myocardial
matrix metabolism and
remodelling.
• Arch Physiol Biochem.
Feb 2012;118(1):31-42.

32. The terrain of the body.
• ECM signaling
–Has also been shown
to help with
immunological
synapse formation in
the immune system.

33. Bibliographic reference.
• Springer TA, Dustin ML.
• Integrin inside-out
signaling and the
immunological synapse.
• Curr Opin Cell Biol.
Feb 2012;24(1):107-115.

34. The terrain of the body.
• Control of the
inflammatory reflex
at the neuro-immune
synapse.

35. Bibliographic reference.
• Dustin ML.
• Signaling at
neuro/immune
synapses.
• J Clin Invest. Apr 2 2012;
122(4):1149-1155.

36. The terrain of the body.
• Inflammation
resolution.

37. Bibliographic reference.
• Widgerow AD.
• Cellular resolution of
inflammation--
catabasis.
• Wound Repair Regen.
Jan-Feb 2012;20(1):2-
7.

38. The terrain of the body.
• Maintenance of
physiological
inflammation.

39. Bibliographic reference.
• Sansonetti PJ.
• To be or not to be a
pathogen: that is the
mucosally relevant
question.
• Mucosal Immunol.
Jan 2011;4(1):8-14.

40. The terrain of the body.
• Information flow
between tissue cells is
also regulated by gap
junction (GJ) proteins,
–which are regulated
by noncoding RNAs.

41. Bibliographic reference.
• Rau F, Freyermuth F,
Fugier C, et al.
• Misregulation of miR-1
processing is associated
with heart defects in
myotonic dystrophy.
• Nat Struct Mol Biol. Jul
2011;18(7):840-845.

42. Bibliographic reference.
• Ye D, Guo S, Al-Sadi R,
Ma TY.
• MicroRNA regulation of
intestinal epithelial tight
junction permeability.
• Gastroenterology.
Oct 2011;141(4):1323-1333.

43. The terrain of the body.
• The involvement
of GJ proteins.
–in the regulation
of stem cell niches.

44. Bibliographic reference.
• Peiris TH, Oviedo NJ.
• Gap junction proteins: Master
regulators of the planarian
stem cell response to tissue
maintenance and injury.
• Biochim Biophys Acta.
Mar 16 2012.

45. The terrain of the body.
• The involvement
of GJ proteins.
–in the protection
of tissue cells from
toxic insults.

46. Bibliographic reference.
• Klee P, Allagnat F,
Pontes H, et al.
• Connexins protect mouse
pancreatic beta cells
against apoptosis.
• J Clin Invest. Dec
2011;121(12):4870-4879.

47. The terrain of the body.
• GJ communication
encompasses a
physiological
phenomenon…
–That modulates cellular
behavior at both the
local and systemic levels

48. Bibliographic reference.
• Peiris TH, Oviedo NJ.
• Gap junction proteins: Master
regulators of the planarian
stem cell response to tissue
maintenance and injury.
• Biochim Biophys Acta.
Mar 16 2012.

49. Microenvironment role.
• Cardinal role of the
microenvironment as
–Cellular information
exchange center
positions
•ECM as a point
of intervention.

50. Bibliographic reference.
• Peiris TH, Oviedo NJ.
• Gap junction proteins: Master
regulators of the planarian stem cell
response to tissue maintenance and
injury.
• Biochim Biophys Acta. Mar 16 2012.

51. Microenvironment / Disease.
• Research supports the
existence of pathological
links between
–The microenvironment
•Diseases such as
cancer.

52. Bibliographic reference.
• Iozzo RV, Sanderson RD.
• Proteoglycans in cancer biology,
tumour microenvironment
and angiogenesis.
• J Cell Mol Med.
May 2011;15(5):1013-1031.

53. Microenvironment / Disease.
• Research supports the
existence of pathological
links between
–the microenvironment
• Poor wound healing.

54. Bibliographic reference.
• Schultz GS, Davidson JM,
Kirsner RS, Bornstein P,
Herman IM.
• Dynamic reciprocity in the
wound microenvironment.
• Wound Repair Regen.
Mar-Apr 2011;19(2):134-148.

55. Microenvironment / Disease.
• Research supports the
existence of pathological
links between
–The microenvironment
•Airway remodeling
disease.

56. Bibliographic reference.
• Burgess JK.
• The role of the extracellular
matrix and specific growth
factors in the regulation of
inflammation and remodelling
in asthma.
• Pharmacol Ther.
Apr 2009;122(1):19-29.

57. Microenvironment / Disease.
• Research supports the
existence of pathological
links between
–the microenvironment
•Hypertensive heart
disease.

58. Bibliographic reference.
• Berk BC, Fujiwara K,
Lehoux S.
• ECM remodeling in
hypertensive heart
disease.
• J Clin Invest. Mar
2007;117(3):568-575.

59. Microenvironment / Disease.
• ECM is involved in the
progression of chronic
disease,
–Fibrotic diseases
•Most solid tumors,
arthritis, osteoporosis,
COPD and emphysema.

60. Microenvironment / Disease.
• Molecules associated
with ECM metabolism
–may serve as
biomarkers for
disease progression.

61. Bibliographic reference.
• Zannad F, Pitt B.
• Biomarkers of
extracellular matrix
turnover.
• Heart Fail Clin.
Oct 2009;5(4):589-599.

62. Microenvironment toxicity.
• Bioaccumulation
of toxins in tissues…
–can negatively
influence cellular
health.

63. Microenvironment toxicity.
• Environmental toxins,
• Metabolic waste products;
–can accumulate
in the ECM…
•and cause disease.

64. Microenvironment toxicity.
• Deficiency,
• Toxicity
–are common etiological
determinants of
contemporary ill-health

66. Bibliographic reference.
• Genuis SJ.
• What's out there
making us sick?
• J Environ Public Health.
2012;2012:605137.

67. Microenvironment toxicity.
• Bioaccumulation of
pesticides in adipose tissue,
–Increases the total body
burden of intoxication and
•May lead to neuro,
immune and
endocrine toxicity.

68. Fig 84

69. Microenvironment toxicity.
• Immune activation
occurs not only
in response to infection,
–Respond to physical,
chemical and genotoxic
tissue stress.

70. Fig 85

71. Microenvironment toxicity.
• Bioaccumulation of
environmental toxins
–Perturbations in the
immune
response/inflammatory
network.

72. Conclusion.
• Fundamental role of
the ECM in cellular
and tissue function…
–Microenvironment
as a key focal point for
therapeutic developments
in bioregulatory medicine.

73. Conclusion.
• Involvement of the
microenvironment
in nearly all
pathological
conditions.

74. Conclusion.
• Microenvironment
information
regulation
–Highly influential
process…
•At local and
systemic levels.