89319 - REGENERATIVE MEDICINE: UNFOLDING THE NANOWORLD OF STEM CELLS TOWARDS A SELF-HEALING POTENTIAL -

Academic Year 2018/2019

  • Docente: Carlo Ventura
  • Credits: 3
  • SSD: BIO/11
  • Language: English
  • Moduli: Carlo Ventura (Modulo 1) Stefano Zanasi (Modulo 2)
  • Teaching Mode: Traditional lectures (Modulo 1) Traditional lectures (Modulo 2)
  • Campus: Bologna
  • Corso: Single cycle degree programme (LMCU) in Medicine and Surgery (cod. 9210)

    Also valid for Second cycle degree programme (LM) in Medical Biotechnology (cod. 8859)

Learning outcomes

We plan to provide Students with clear-cut evidence that Regenerative Medicine is not simply a hope for the future, but it is now successfully applied in multiple medical contexts. There is compelling evidence that different regenerative approaches, as those discussed from a molecular point of view by Prof. Ventura, can be remarkably translated into the Orthopaedic fields. Within this context, the issue of obtaining tissue derivatives (i.e. the human adipose tissue) processed to a microfractured tissue encompassing an intact stromal-vascular niche with elements of pericyte/mesenchymal stem cell identity, represents a vivid example of the clinical application of concepts viewing the "niche" as a nanotopography bearing physical and chemical cues essential for unfolding the regenerative potential of niche-enclosed regenerative cells. The finding that these cells are primarily pericytes, the actual source for MSCs in vivo, also involves important clinical outcomes. We will finally discuss the clinical application of a relevant part of the course, that is the use of physical energies to reprogram in situ the tissue resident stem cells to maximize their rescuing potential, both in the absence or presence of cell/tissue transplantation. We expect that Students attending this elective course will become able to use the acquired knowledge to boost their curiosity on the most recent and fascinating breakthrough in stem cell biology. We also expect that, from expanding their “vocabulary” of knowledge the Attendants will have the chance to understand or even perform/being involved in research activities paving the way to novel approaches in (stem) cell reprogramming and tissue regeneration. Accordingly, another expected ability is the chance of participating in or applying to research programs in cell therapy and regenerative medicine at both national and international level

Course contents

Background

Progress in understanding stem cell biology is holding promise for a novel perspective in the cure of diseases that cannot be currently approached even by the most advanced pharmacological or surgical interventions. The emerging chance for a Regenerative Medicinetailored on patient-specific unmet clinical needs may prelude to the unprecedented opportunity for a Precision Medicine.

There is now increasing evidence that cells are also governed by physical energies and that cell biology entails circadian rhythms that are fashioned at multiple interconnected levels, involving the generation of cellular electric (and most likely electromagnetic) fields, mechanical oscillations, and electromagnetic radiation (light). Biomolecular recognition patterning not only occurs through lock/key interactions but it is based upon resonance modes and synchronization of vibrational patterns at molecular and supramolecular level.

Cell sensitivity to physical energies is forming the underpinning to exploit the diffusive feature of such energies to target and reprogram our stem cells where they already are, in all tissues of the human body, resuming our inherent ability for self-healing. Seeing (stem)cell biology with the eyes of Physics may therefore promote a new paradigm for a Regenerative Medicine developed without the needs for cell or tissue transplantation.

 

The core knowledge

  1. Advanced dissection of the biophysical mechanisms impacting on stem cell dynamics.
  2. Recent discoveries on the role of microtubli and cytoskeletal networks in the generation and unfolding of informational processes responsible for stem cell pluripotency, commitment and terminal differentiation.
  3. Microtubuli as a bioelectronic circuit in cell signaling network.
  4. Viewing the inter-cellular communication as processes mainly executed through the release and exchange of signaling molecules packaged inside a network of nanovescicles, embedding small peptides, microRNA, long-chain RNA and probably DNA.
  5. Discussing how, rather than communicating through the secretion of naked molecules, cells and stem cells adopt the exchange of pockets of information, even through the establishment of an intercellular nanotube network.
  6. The role of “stem cell niche”. Stem cells are not simply “sitting” in our tissues, but they live within the context of a very specialized architecture, the niche. The stem cell nicheis a pro-active environment defined at the nano-scale level, a nanotopography encrypting both chemical and physical cues essential to exploit the regenerative potential of stem cells.
  7. The relevance of preserving such nanotopography (i.e. the integrity of stem cell niche) in tissues transplantable for regenerative purposes (i.e. bone marrow, fat): a strategy to increase the chance for structural and functional recovery of damaged organs.
  8. The identification of natural or the development of artificial scaffolds capable to mimic the niche: a major area of enquiry to optimize the outcome from stem cell transplantation and tissue engineering.
  9. The relevance of stem cell aging as a crucial feature counteracting our innate self-healing ability.
  10. The use of physical energies, including nano-mechanical vibration, electric and electromagnetic fields, electromagnetic radiation – light and “photobiomodulation” to govern stem cell pluripotency, commitment and terminal differentiation.
  11. Stem cell reprogramming.
  12. Somatic cell reprogramming to embryonic like intermediate: a novel path in tissue regeneration.
  13. The use physical energies to reverse stem cell aging: the telomerase – independent and the telomerase dependent pathway.
  14. The chance of deploying the diffusive features of physical energies to target stem cells where they already are, residing in all tissue of the human body: affording stem cell reprogramming and tissue healing without the needs for stem cell transplantation.

On the whole, the proposed elective course is focused on novel, emerging paradigms in cell biology and tissue regeneration, discussing the current efforts to unfold the nanoworld of stem cells towards a self-healing potential.

 

Clinical Unfolding and Application of Regenerative Medicine

The course aims at providing compelling evidence that Regenerative Medicine is becoming a clinical reality and that Regenerative Orthopedic Surgery is one of the fields in which Regenerative Medicine has been first unfolded.

We will show that wide areas of severe cartilage defects due to osteoarthritis of the inferior limb, in particular knee and ankle, can be successfully restored through transplant of human bone marrow combined with defined human fat tissue products.

We will focus on the relevance of yielding fluid fat tissue derivatives containing an intact stromal vascular niche, a stem cell nanotopography including elements of pericyte identity.

We will highlight that mesenchymal stem cells (MSCs), acting as major conductors for tissue regeneration in vivo, reside in the niche in the form pericytes, a cell type that is turned into MSCs upon the intervention of tissue injuries.

We will show that it is now possible to develop nanofabricated scaffolds with tailored-oriented architecture and fiber diameter.

We will provide evidence that the combinatorial use of human bone marrow and fat tissue derivatives, embedded in such scaffolds, yields a significantly more enhanced cartilage regeneration, as compared with the rescuing effects elicited by either bone marrow or a fat derivative alone.

We will show how to document all these clinical outcomes by 1.5T NMR, elastosonography and in randomized histological analyses. These diagnostic tools reveal a higher percentage of hyaline cartilage and rare fibrous tissue compared to the outcome of the single, not combined procedures. On these bases, the combined use of autologous non-expanded tissue products made of whole bone marrow and human white adipose tissue derivatives, can be considered as an autologous/homologous strategy for improving the natural capacity for self-healing in damaged osteo-articular tissues.

 

Detailed Program

Basic and Translational Research (Prof. Carlo Ventura)

  1. The cytoskeleton: microtubuli as an oscillatory network spreading nanomechanical forces, electric and electromagnetic fields. Microtubli as a bioelectronic circuit for the emerging of informational processes involved in (stem) cell pluripotency, commitment and differentiation.
  2. Cell emission of electromagnetic radiation (light).
  3. Photobiomodulation: a novel emerging field in the control of stem cell fate and tissue regeneration.
  4. The link between nucleoskeleton and cytoskeleton.
  5. Seeing gene transcription in the light of nanomechanics.
  6. The role of stemness genes and molecular motors in stem cell biology.
  7. Epigenetics and stem cell fate.
  8. Governing stem cell biology with natural or synthetic molecules.
  9. The use of developmental stage cocktails of embryonic molecules derived from highly regenerative organisms (Zebrafish, Mexican Axolotl) to reprogram and enhance stem cell potency and differentiation: shrinking evolutionary distances.
  10. The use of physical energies, including nanomechanical vibration, electromagnetic fields and light to efficiently reverse stem cell aging.
  11. The use of physical energies, including nanomechanical vibration, electromagnetic fields and light for tuning stem cell potency and differentiation.
  12. Physical tissue stimulation: a pathway for self-healing and tissue regeneration without the needs for (stem) cell transplantation.

 

Clinical Applications (Prof. Stefano Zanasi)

  1. Background on cartilage defects, and their inherent clinical challenges: the origin of Regenerative Orthopedic Surgery.
  2. The adipose tissue as a source for regenerative processes.
  3. The paracrine effect and the exosome nanoworld.
  4. New generation technologies in human fat processing for regenerative purposes.
  5. The personal experience.
  6. Combinatorial use of bone marrow and fat tissue derivatives. The use of nanopatterned scaffolds embedding the tissue mixture.
  7. Unfolding the regenerative cues of bone marrow and adipose tissue through the reconstruction of tissue nanotopography. Evidence for cartilage regeneration.
  8. Conclusions: adipose tissue combined with bone marrow for the treatment of coin, complex and contained kissing lesions (OA) of knee, ankle and shoulder, concurrently with realignment procedures, can be considered a safe and highly effective therapeutic option.

Readings/Bibliography

Throughout the course we will discuss emerging research articles and reviews, readily available from PUBMED.

Main findings from the most recent and worldwide relevant meetings will be presented and discussed, as a vivid example of bleeding-edge discoveries that are not yet published

Teaching methods

Teaching Methods will be based upon the discussion of:

  • The major interconnection between subject of Students’ curiosity and each of the issued discussed during the lessons.
  • The most important solutions and problems arising from some of the most advanced views in cellular signaling, genome function and cellular reprogramming.
  • The most updated publications within the context of Molecular and Cellular Biology, with particular emphasis to mechanisms underlying cellular commitment and adaptation, reprogramming, and differentiation.
  • The major chances for clinical translation of relevant issues in basic Science.
  • The chance that progress in basic and translational research may ffectively match unmet clinical needs.
  • Attendance to learning activities is mandatory; the minimum attendance requirement to be admitted to the final exam is 66% of lessons.Professors may authorise excused absences upon receipt of proper justifying documentation, in case of illness or serious reasons. Excused absences do not count against a student’s attendance record to determine their minimum attendance requirement.

Assessment methods

At the end of the Course, we will verify whether the Students will be able to:

  • Provide a critical/personalized discussion of the main issues addressed throughout the course.
  • Show the capability of a critical readings of relevant publications appearing in PubMed, becoming able of merging their curiosity with defined and proper “key words”.
  • Organize themselves into small groups of studies, and then present short seminars to the audience of their Colleagues.
  • Prompt/stimulate a collegial and critical discussion of subjects of mutual interest.

Teaching tools

  • Power point presentations.
  • Critical discussion of personal research and review articles.
  • Critical readings of studies published by other Authors.
  • Presentation of movies from international meetings.
  • Presentation of movies from basic and translational research in Regenerative Medicine.
  • Presentation of movies from Regenerative Orthopedic Surgery.

Office hours

See the website of Carlo Ventura

See the website of Stefano Zanasi