Regenerative Medicine – Cellular Medicine

Cellular Medicine is the advanced medicine based on the application of stem cells which are present inside the body. This has the enormous potential in the new treatment methodologies of the diseases and disorders.Autologous cellular therapy means use of patient's own body stem cells for his/her treatment

Inside of our body there is a microscopic world – busy and complex. This world is made up of stem cells. Stem cells which are nothing but the building blocks of the body are the steps of the ladder of Regenerative Medicine. These stem cells are capable of differentiating into different types of cell lines and thus hold a promise to cure number of the medical conditions subjected to physician's approval.

Stem Cells types

-Totipotent (total):
  • Total potential to differentiate into any adult cell type
  • Total potential to form specialized tissue needed for embryonic development -Pluripotent (plural): Multipotent (multiple):
  • Limited potential
  • Forms only multiple adult cell types
  • Stem Cells Sources
  • -Embryonic Stem Cells (ESC): received from:
  • Embryos created in vitro fertilization
  • Aborted embryos
  • -Adult Stem Cells (ASC): can be received from:
  • Limited tissues (bone marrow, muscle, brain, adipose tissue)
  • Discrete populations of adult stem cells generate replacements for cells that are lost      through normal wear and tear, injury or disease.
  • Placental cord

What are hematopoietic stem cells?

A hematopoietic stem cell is a cell isolated from the blood or bone marrow that can renew itself, can differentiate to a variety of specialized cells, can mobilize out of the bone marrow into circulating blood, and can undergo programmed cell death, called apoptosis—a process by which cells that are detrimental or unneeded self-destruct.

Bone Marrow (Soft, gelatinous tissue that fills the medullar cavities - the centers of bones.)

There are two types of bone marrow:

  • Red bone marrow (also known as myeloid tissue)
  • Yellow bone marrow (fatty tissue).
  • Both types of bone marrow are highly vascular and enriched with numerous blood vessels and capillaries.

    The bone marrow makes more than 200 billion new blood cells every day.8 Most blood cells in the body develop from cells in the bone marrow.5

    Stem cells in Bone Marrow

    The bone marrow has two types of stem cells: mesenchymal and hematopoietic. Red bone marrow consists of a delicate, highly vascular fibrous tissue containing hematopoietic stem cells, which are blood-forming stem cells. Yellow bone marrow contains mesenchymal stem cells, also known as marrow stromal cells, which produce fat, cartilage and bone. Stem Cells in bone marrow can renew and differentiate. Through hematopoietic differentiation these pluripotent stem cells can form different blood cells. Mesenchymal stem cells found in the bone marrow cavity and differentiate into a number of stromal lineages, such as chondrocytes (cartilage generation), osteoblasts (bone formation), osteoclasts, adipocytes (adipose tissue), myocytes (muscle), macrophages, endothelial cells and fibroblasts.

    Stem cells constantly divide and produce new cells. Some new cells remain as stem cells and others go through a series of maturing stages (precursor or blast cells) before forming into fully formed (mature) blood cells. Stem cells rapidly multiply to make millions of blood cells each day.

    Blood cells have a limited life span and are constantly being replaced. The production of healthy stem cells is vital.The blood vessels constitute a barrier, inhibiting immature blood cells from leaving the bone marrow. Only mature blood cells contain the membrane proteins required to attach to and pass the blood vessel endothelium. Hematopoietic stem cells may also cross the bone marrow barrier, and may be harvested from blood.

    Once mature, these blood cells migrate from the marrow and are introduced into the bloodstream, where they provide important functions in keeping the body alive and healthy.

    Facts of Bone Marrow

  • At birth, all bone marrow is red. As humans age, red marrow increasingly begins to convert to yellow marrow.
  • In adults, around half of the bone marrow is red and half is yellow.
  • 200 billion new blood cells are made by the bone marrow every day.
  • Healthy bone marrow manufactures between 150,000 and 450,000 platelets per micro liter of blood, the amount of blood that fits on the head of a pin.
  • Bone marrow contains mesenchymal and hematopoietic stem cells.
  • Peripheral Blood

    PRP (Platelet rich plasma) with increased number platelets and growth factors has the potential to augment the healing process and stimulate regeneration. Enriched with the growth factors and proteins, PRP can be the effective solution for the treatment of number of orthopaedic conditions. The cytokines released from PRP, can effectively act on cells which helps them in differentiating into different cell lineages. Further it is interesting to know that Platelet released growth factors play an important role in activating the signalling pathways for stem cells to reach at the target site of injury in orthopaedic conditions. In this review, we have investigated the factors which are responsible for making PRP as a medical solution to Orthopaedic conditions.

    Platelets are discoid shaped, approximately 2µm in size enucleated cytoplasmic fragments formed by megakaryocytes in Bone marrow. They are comprised of organelles such as mitochondria , microtubules and granules (α,β,λ). There are approximately 50-80 microvesicles of 300-500nm size present in each platelet. The granules α,β,λ each have different fundamental role in contributing towards the primary function of platelets which is homeostasis and wound healing. α granules release presynthesized bioactive proteins which includes adhesive proteins ,adhesive proteins ,growth factors immediately after platelet activation. β granule contains Ca,Mg,Adenosine,Serotonin that promotes clotting of blood. λ granule is considered as the lysosomal type organelle which is responsible in removing cellular debris or infection causing agent.

    Post an injury or trauma to the blood vessels, platelets get exposed to the subendothelial structures promoting platelet adhesion to the basement membrane of damaged capillariesand aggregate to form a platelet plug, this process is defined as platelet activation. α granules on activation release their contents which bind to the transmembrane receptors on the target cells initiating a cascade mechanism for healing.

    Platelet Rich Plasma

    This natural healing process may be sufficient in case of small defects, however if the damage is extensive a treatment method which could accelerate the repair is needed .PRP is a novel approach used recently that has the potential to augment the healing process and stimulate regeneration .Platelet Rich Plasma (PRP) is a volume of autologus plasma that has platelet concentration above baseline. Normal Platelet count in blood range is 150,000 /µl to 350,000/µl. PRP has increased number of platelets thus contains increased number of Growth Factors. The known growth factors present in PRP are Platelet Derived Growth Factor (PDGF), Transforming Growth Factor-β (TGF-β), Vascular Endothelial Growth Factor(VEGF), Endothelial Growth Factor(EGF), Fibroblast Growth Factor(FGF), Interstitial Growth Factor(IGF). PRP is considered as the reservoir of growth factors which could augment wound healing and regeneration of bone in the orthopaedic conditions. There is burst of Growth factors immediately after platelet activation, after which it continues to secrete such factors till their lifespan. PRP contains additional proteins that include fibronectin, fibrin, vitronectin Cell adhesion molecules required for the migration of osteoblast, fibroblast towards the target site. These target cells involved in healing express intracellular receptors on the Cell membrane which enables the platelet released Growth factors to bind and activate the signalling pathway.

    Cascade events involved in bone formation are chemotaxis, cell migration, proliferation and Osteogenic differentiation which are facilitated by the growth factors. PDGF and TGFβ are the first growth factors to be released after the clotting of PRP. They are chemotactic in nature that can recruit the MSC's and progenitor cells to the target site and stimulate cell proliferation. Osteogenic differentiation of progenitor cells is controlled by TGFβ, IGF and Bone Morphogenetic Proteins (BMP) . VEGF enhances the blood circulation in the target site necessary for healing and repair by stimulating angiogenesis.

    PRP is easy, minimally invasive, and safe procedure. The contents of PRP are normal body proteins comparable to the blood clot released growth factors in normal wound, with an exception of greater concentration in PRP thus excluding the risk of acquiring any infection or immune reaction.

    Cellular Medicine: Bone Marrow and PRP – effective combination against several diseases and disorders