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 Table of Contents  
Year : 2016  |  Volume : 6  |  Issue : 1  |  Page : 1-2

In situ vasculogenesis: The potential role of mesenchymal stem cells in craniofacial reconstruction

Department of Surgery, Division of Plastic Surgery, Saint Louis University, Saint Louis, MO 63103, USA; Department of Surgery, National Autonomous University of Nicaragua; Department of Surgery, Hospital Metropolitano Vivian Pellas, Managua, Nicaragua

Date of Web Publication12-Jul-2016

Correspondence Address:
Michael H Carstens
Department of Surgery, Division of Plastic Surgery, Saint Louis University, Saint Louis, MO 63103; Department of Surgery, National Autonomous University of Nicaragua; Department of Surgery, Hospital Metropolitano Vivian Pellas, Managua

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DOI: 10.4103/2231-0746.186147

PMID: 27563596

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How to cite this article:
Carstens MH. In situ vasculogenesis: The potential role of mesenchymal stem cells in craniofacial reconstruction. Ann Maxillofac Surg 2016;6:1-2

How to cite this URL:
Carstens MH. In situ vasculogenesis: The potential role of mesenchymal stem cells in craniofacial reconstruction. Ann Maxillofac Surg [serial online] 2016 [cited 2020 Aug 12];6:1-2. Available from:

Many years ago, UCLA orthopedic surgeon Marshall Urist, working on what became recombinant human bone morphogenetic protein 2 (rhBMP-2), envisioned that rhBMP-2 would be destined to bring the control of bone formation into the hands of spine surgeons. His student, Phil Boyne at Loma Linda University extended the use of rhBMP-2 forward in membranous bone defects, the mechanism being a stimulation of periosteal stem cells into an osteogenic lineage. In 2001, an unusual case of multiple facial clefts accompanied by a unilateral absence of the ramus and condyle 2001 was treated by this author and Dr. Martin Chin at the Children's Hospital of Northern California with an implant of rhBMP-2 under Food and Drug Administration approval for compassionate use. The defect was successfully reconstructed; we termed the process in situ osteogenesis (ISO) and reported the case in 2005.[1],[2] The characteristics of ISO – generated bone were further defined when the operative site was re-explored, osteotomized, and distracted.[3] Larger defects of craniofacial bone have been subsequently reconstructed using ISO.[4]

Full scale implementation of rhBMP-2 in maxillofacial surgery and periodontology (for alveolar ridge augmentation and sinus lift) remained elusive, in part due to the expense of the recombination technology involved. Nonetheless, many lessons remained. First, use of rhBMP-2 implants was accompanied by a rapid vascular response. This is not surprising, given that craniofacial periosteum is derived from neural crest, given that mesenchymal stem cells (MSCs) are related to neural crest and given that MSCs produce vascular endothelial growth factor.[5],[6] Second, scars formed in soft tissues overlying these implants were difficult to notice, with little inflammation; this is attributable to the anti-inflammatory properties of MSCs in vivo. Third, overlying soft tissues were softer than anticipated; this again is due to the anti-fibrotic properties of MSCs. I came to the conclusion that the effectiveness of rhBMP-2 to create bone was utterly dependent upon the presence of responder MSCs in adequate numbers; furthermore that the soft tissue response seen was due to the paracrine effect of bioactive factors produced by MSCs.[7]

Implantation of MSCs is now a clinical reality.[8],[9] MSCs have been shown to occupy a perivascular niche; their cell of origin being the ubiquitous pericyte, perhaps the most important and least understood cell in developmental biology.[10] The pericyte is structurally and chemically related to neural crest; these cells have contractile fibers and are under the control of the sympathetic autonomic nervous system, a system embryologically derived exclusively from the neural crest. Molecular markers on the cell membranes of MSCs called the cluster of differentiation markers (CD) demonstrate the relationship between MSCs and pericytes.[11]

The existence of MSCs in adipose tissue was first reported by Zuk et al. in 2001.[12] These cells are essentially identical with those residing in bone marrow, save for their difference in number, adipose-derived stem cells (ASCs) being ×500 more common than bone marrow MSCs. The putative cell leading to the development of white fat is the pericyte – brown fat originates from paraxial mesoderm – and this may explain this phenomenon. The biology of stem cells.

Contemporary technology permits the collection of ASCs in large numbers via conventional liposuction plus enzymatic digestion using collagenases followed by centrifugation.[13] New techniques for the nonenzymatic processing of fat using mechanical disruption have been developed; these will be coming online in the near future as well. When ASCs are processed by current means, they form a part of the so-called stromal vascular fraction (SVF) in combination with pericytes, fibroblasts, and endothelial precursor cells. When SVF is transplanted autologously, it has the following major characteristics: (1) Vascular induction, (2) anti-fibrosis, (3) anti-inflammation, (4) anti-microbial through novel mechanisms, (5) production of multiple paracrine factors, (6) a cell-saving or anti-apoptotic effect, and (7) regenerative effect with MSCs potentially responding to differentiation cues from the local environment to develop a given cell line, that is, when implanted into a tendon injury to form tenocytes.

In craniomaxillofacial surgery, the implantation of adipose-derived MSCs lends itself readily to a diverse number of problems. The vascular induction capability combined with an osseous framework could lend itself to bone reconstruction such as alveolar ridge augmentation, sinus lift, protection of failing implants, mandible/craniofacial defects, nonunion, and osteoradionecrosis. Temporomandibular joint problems could benefit from the reduction of existing fibrosis, the prevention of fibrosis in primary surgery, and possibly the regeneration of the disc itself. Finally, the paracrine effects of MSCs on soft tissues can provide for in situ revascularization both for the preparation of flaps prior to transfer as well as to flap salvage in cases of ischemia or swelling.

From this perspective, the possibilities for further dental research into the effects of MSCs, be they from fat or bone marrow, are very real, very do-able, involve relatively low levels of technology, and are inexpensive. The payoff from such research efforts is destined to bring the control of soft tissues and bone into the hands of clinicians with untold benefits for patients in the future.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Carstens MH, Chin M, Li XJ. In situ osteogenesis: regeneration of 10-cm mandibular defect in porcine model using recombinant human bone morphogenetic protein-2 (rhBMP-2) and Helistat absorbable collagen sponge. J Craniofac Surg 2005;16:1033-42.  Back to cited text no. 1
Carstens MH, Chin M, Ng T, Tom WK. Reconstruction of #7 facial cleft with distraction-assisted in situ osteogenesis (DISO): role of recombinant human bone morphogenetic protein 2 (rhBMP-2) and Helistat activated sponge. J Craniofac Surg 2005;16:1023-32.  Back to cited text no. 2
Tom WK, Chin M, Ng T, Bouchoucha S, Carstens M. Distraction of rhBMP-2-generated mandible: how stable is the engineered bone in response to subsequent surgeries? J Oral Maxillofac Surg 2008;66:1499-505.  Back to cited text no. 3
Chao M, Donovan T, Sotelo C, Carstens MH. In situ osteogenesis (ISO) of hemimandible with recombinant human bone morphogenetic protein 2 (rhBMP-2) in a 9 year old boy: osteoconduction via stem cell concentration. J Maxillofac Surg 2006;17:405-12.  Back to cited text no. 4
Thomas S, Thomas M, Wincker P, Babarit C, Xu P, Speer MC, et al. Human neural crest cells display molecular and phenotypic hallmarks of stem cells. Hum Mol Genet 2008;17:3411-25.  Back to cited text no. 5
Bautch VL. Stem cells and the vasculature. Nat Med 2011;17:1437-43.  Back to cited text no. 6
Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell 2011;9:11-5.  Back to cited text no. 7
Brown SA, Levi B, Lequeux C, Wong VW, Mojallal A, Longaker MT. Basic science review on adipose tissue for clinicians. Plast Reconstr Surg 2010;126:1936-46.  Back to cited text no. 8
Gir P, Oni G, Brown SA, Mojallal A, Rohrich RJ. Human adipose stem cells: Current clinical applications. Plast Reconstr Surg 2012;129:1277-90.  Back to cited text no. 9
Armulik A, Genové G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 2011;21:193-215.  Back to cited text no. 10
Amos PJ, Shang H, Bailey AM, Taylor A, Katz AJ, Peirce SM. IFATS collection: The role of human adipose-derived stromal cells in inflammatory microvascular remodeling and evidence of a perivascular phenotype. Stem Cells 2008;26:2682-90.  Back to cited text no. 11
Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001;7:211-28.  Back to cited text no. 12
Katz AJ, Miricili AF. Stem cells derived from fat. In: Atala A, Lanza R, editors. Principles of Regenerative Medicine. New York: Elsevier; 2011. p. 365-81.  Back to cited text no. 13


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