The Future Role of Stem Cells in Antimicrobial

The Future Role of Stem Cells in Antimicrobial

The Future Role of Stem Cells in Antimicrobial Therapies KHALID AL-ANAZI Dubai November 2015 Topics to be covered 12345- Introduction to various types of stem cells. Mesenchymal stem cells (MSCs): Sources & distinguishing features

Evolving clinical indications Complications of MSCs & existing challenges Tracking of MSCs final conclusions Types of Stem Cells (1) Totipotent stem cells: zygote + [2 to 4] cell embryo - Capable of giving rise to the entire organism (embryonic and non-embryonic tissues) (2) Multipotent stem cells; adult stem cells: ** Mesenchymal stem cells (3) Pluripotent stem cells: embryonic stem cells & embryonic germ cells: * Can give rise to derivatives of all 3 germ layers

* There are 2 types of pluripotent stem cells (PSCs): [a] Embryonic stem cells (ESCs): - Derived from the inner cell mass of the mammalian blastocyte. - Have the potential to form any cell type in the body. [b] Induced pluripotent stem cells (iPSCs): - Somatic cells reprogrammed to a pluripotent state by exogenous expression of transcription factors. - Liras A, et al. In-Tech 2013 - Arora N, et al. Cold Spring Harb Perspect Med 2012 Sources of MSCs 1- Bone marrow 2- Peripheral blood

3- Blood of umbilical cord, Whartons jelly of UC 4- Placenta & fetal membrane 4- Amniotic fluid & amniotic membrane 5- Synovial fluid 6- Dental tissues e.g. pulp 7- Palatal tonsil; salivary glands 8- Fallopian tubes; endometrium 9- Fat: adipose tissue 10- Parathyroid glands 11- Skin & foreskin - Wang Y, et al. Stem Cell Int 2012 - Ra JC, et al. Stem Cell Dev 2011 - Ullah I, et al Bioscience Rep 2015 [In Press]

- Herberts CA, et al. J Transl Med 2011 - Wong RSY, et al. J Biomed Biotechnol 2011 - Al-Anazi KA, et al. In-Tech 2015 [In Press Distinguishing features of MSCs (A) They must be plastic adherent (B) They must be capable of differentiating into: osteoblasts, adipocytes and chondrocytes (C) Findings on flow cytometry: [1] positive surface molecules: - CD 105

- CD 29 - CD 73 - CD 44 - CD 90 - CD 166 [2] negative surface molecules: - CD 45

- CD 34 - CD 14 - CD 11 - CD 19 - CD 79 - HLA DR - CD 31

- Wang Y, et al. Stem Cell Int 2012 - Herberts CA, et al. J Transl Med 2011 - Ra JC, et al. Stem Cell Dev 2011 - Wong RSY, et al. J Biomed Biotechnol 2011 - Al-Anazi KA, et al. In-Tech 2015 [In Press] - Zomer HD et al Stem Cell Clon 2015

Clinical trials using MSCs Numbers of registered clinical trials on MSC-based therapies 1- 2004 0.0 2- 2010 58 3- 2012

130 4- 2014 463 - Wei X, et al. Acta Pharmacol Sinica 2012 - Ullah I, et al Bioscience Rep. 2015 [In Press] Clinical trials in 2014 [463] 1- Myocardial infarction 70

2- Autoimmune disorders 45 3- Liver cirrhosis 32 4- Graft versus host disease 29

5- Spinal cord injuries 15 - Ullah I, et al Bioscience Rep. 2015 [In Press] Clinical diseases treated by MSCs; 2012 Therapeutic indications of MSCs 1- In stem cell transplantation: - Prevention & Rx of graft versus host disease - Enhancement of engraftment 2- In cardiology; treatment of:

- Coronary artery disease - Myocardial infarction - Dilated cardiomyopathy 3- Critical limb ischemia 4- Repair of skeletal tissues 5- Non-healing chronic wounds 6- Chronic spinal cord injuries 7- Liver injury 8- Regenerative medicine 9- Osteogenesis imperfecta 10- Amyotrophic lateral sclerosis 11- Acute respiratory distress syndrome 12- Severe autoimmune disorders: SLE, RA, MS & systemic sclerosis

- Wang Y, et al. Stem Cell Int 2012 - Ra JC, et al. Stem Cell Dev 2011 - Al-Anazi KA, et al. In-Tech 2015 [In Press] - Herberts CA, et al. J Transl Med 2011 - Wong RSY, et al. J Biomed Biotechnol 2011 Conclusions from experimental sepsis models & human clinical trials Conclusions continued Conclusions continued

Accepted roles MSCs during infection Details and explanations Main effect / mechanism Phase - Engagement of TLR-mediated signaling pathways Detection of pathogens and damage 1 - Recruitment of MSCs at the sites of infection

signals - Maintenance of quiescent HSC pool Activation of host immune response 2 Elimination of pathogens 3 - BM emigration of activated HSCs

- Mobilization and emigration of immune effector cells from BM. - Thymic development to augment response of immune effector cells - Production of microbiocidal soluble factors - Containment of infectious pathogen within micro-environment [ pathogen phagocytosis ] - Antioxidant soluble factor (HO-1) Induction - Antiinflammatory soluble factors such as: IDO, PGFZ, IL-10, gradients

of pro-inflammatory 4 TGF-B, TGF-6, HLA-G5 and Galectin-1 - Activation of function, differentiation and migration of immune effector cells. - Augmentation of wound healing - Enhancement of revascularization - Inhibition of tissue toxicity - Modulation of inflammation and organ dysfunction.

Modulation of pro-inflammatory host 5 immune response MSCs in M. TB Infections Auto-MSCT in TB Auto-MSCT in TB continued MSCs in HSCT MSCs in HSCT continued

Other Studies on MSCs in HSCT ** 3 studies on the use of MSCs in Rx of steroid-refractory GVHD & 2 studies on the use of MSCs in GVHD prevention showed no increase in the incidence of viral, bacterial or fungal infections. - Kurtzberg J et al Biol BMT 2013 Fang B et al Transplant Proc 2007 Lucchini G et al Stem Cell Int 2012

- Baron F et al Biol BMT 2010 - Ball LM et al Blood 2007 New data on GVHD MSCs and Viral Infections MSCs in HIV-1 infection Auto-BM-MSCs in Liver Failure due to Hepatitis B Auto-BM-MSCs in Liver Failure due to Hepatitis B Infection 527 patients with liver failure recruited Study had 2 arms: Transplantation [53 patients] & Control [105 patients]

** Transplantation Arm [Auto-BM-MSCs]: 120 ml of BM were obtained, diluted then separated BM-MSCs were slowly transfused through hepatic arteries Procedure was successful & no immediate side effects encountered T. Bil, Albumin, PT & Liver Enzymes improved within 2-3 weeks of Tx No significant difference in long-term outcome. Peng L et al Hepatology 2011 Tracking of Stem cells Tracking of stem cells continued Tracking of stem cells continued

Conclusions - Stem cells including MSCs may become very promising novel therapeutic for various infections in high-risk patients in the near future. - MSCs may reshape the future of antimicrobial therapies and may become curative for several chronic and intractable infections. -

However, this field is still in its infancy and plenty of research & clinical trials are required to refine the therapeutic roles of MSCs. - Complications related to stem

cell therapies should not be underestimated. -

The remaining challenges facing the clinical applications of MSCs need to be resolved. - Banking of MSCs is vital to make them readily available for use. - For collection, culture, cryopreservation & clinical utilization of MSCs, strict guidelines, standardization of techniques & quality control measures are vital.

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